bluuebunny/crossref_metadata_2025 huggingface dataset:
Antioxidant Therapeutics in Parkinson’s Disease: Current Challenges and Opportunities
Authors: Duarte-Jurado Ana Patricia , Gopar-Cuevas Yareth , Saucedo-Cardenas Odila , Loera-Arias Maria de Jesus , Montes-de-Oca-Luna Roberto , Garcia-Garcia Aracely , Rodriguez-Rocha Humberto
Published: March 2021

Oxidative stress is considered one of the pathological mechanisms that cause Parkinson’s disease (PD), which has led to the investigation of several antioxidants molecules as a potential therapeutic treatment against the disease. Although preclinical studies have demonstrated the efficacy of these compounds to maintain neuronal survival and activity in PD models, these results have not been reflected in clinical trials, antioxidants have not been able to act as disease modifiers in terms of clinical symptoms. Translational medicine currently faces the challenge of redesigning clinical trials to standardize criteria when testing molecules to reduce responses’ variability. Herein, we discuss current challenges and opportunities regarding several non-enzymatic antioxidants’ therapeutic molecules for PD patients’ potential treatment.
The Medical Outcomes Distribution and the Interpretation of Clinical Data Based on C4.5 Algorithm for the RCC Patients in Taiwan
Authors: Lee Hsi-Chieh , Liu Ju-Hsia , Ho Ching-Sung
Published: March 2021

The aim of our study is to explore the medical outcomes among patients in the respiratory care center (RCC) and related factors. A cross-sectional study was performed at a regional hospital in central Taiwan from January 2018 to December 2018. The sample consisted of 236 patients who received RCC medical services. The chi-square test, multiple ordinal logistic regression analyses, and C4.5 decision tree algorithm were performed. The risk factors for medical outcomes in critical or deceased patients were obesity (BMI ≥ 27.0) (OR = 2.426, 95% C.I. = 1.106–5.318, p = 0.027), being imported from home (OR = 2.104, 95% C.I. = 1.106–3.523, p = 0.005), and with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 25 (OR = 2.640, 95% C.I. = 1.283–5.433, p = 0.008). The results of the C4.5 algorithm showed a precision of 79.80%, a recall of 78.80%, an F-measure of 78.20%, a receiver operating characteristic curve (ROC) area of 89.20%, and a precision-recall curve (PRC) area of 81.70%. It is important to design effective intervention strategies for patients who are obese and with high APACHE II scores and propose timely treatments for the patients’ onset of disease at home. Moreover, by using the C4.5 algorithm, data can be interpreted in terms of decision trees to aid the understanding of the medical outcomes of the RCC patients.
An RNA Triangle with Six Ribozyme Units Can Promote a Trans-Splicing Reaction through Trimerization of Unit Ribozyme Dimers
Authors: Akagi Junya , Yamada Takahiro , Hidaka Kumi , Fujita Yoshihiko , Saito Hirohide , Sugiyama Hiroshi , Endo Masayuki , Matsumura Shigeyoshi , Ikawa Yoshiya
Published: March 2021

Ribozymes are catalytic RNAs that are attractive platforms for the construction of nanoscale objects with biological functions. We designed a dimeric form of the Tetrahymena group I ribozyme as a unit structure in which two ribozymes were connected in a tail-to-tail manner with a linker element. We introduced a kink-turn motif as a bent linker element of the ribozyme dimer to design a closed trimer with a triangular shape. The oligomeric states of the resulting ribozyme dimers (kUrds) were analyzed biochemically and observed directly by atomic force microscopy (AFM). Formation of kUrd oligomers also triggered trans-splicing reactions, which could be monitored with a reporter system to yield a fluorescent RNA aptamer as the trans-splicing product.
Effects of Flexural Stiffness on Deformation Behaviour of Steel and FRP Stress-Ribbon Bridges
Authors: Juozapaitis Algirdas , Sandovič Giedrė , Jakubovskis Ronaldas , Gribniak Viktor
Published: March 2021

Stress-ribbon systems develop the most flexible and slender bridges. A structural system of such elegant bridges consists of cables or ribbons and deck slabs placed to these strips to distribute the live load. Although this structural system is simple, the design of such structures is a challenging issue. Design limitations of the bridge deck slope induce considerable forces in the ribbons, which transfer the tension to massive foundations. The deformation increase under concentrated and asymmetrical loads causes another problem of stress-ribbon bridges—the kinematic component, the design object of such structures, exceeds the dead load-induced vertical displacement several times. This paper introduces a new concept of such a structural system, comprising ribbons made of flexural-stiff profiles. The proposed approach to reduce kinematic displacements is illustrated experimentally by testing two pedestrian bridge prototypes with different flexural stiffness of the steel ribbons. Numerical models calibrated using the test results are used for the parametric analysis of the flexural stiffness effect on the deformation behaviour of the bridge system with steel and fibre-reinforced polymer (FRP) ribbons. A practical approach to the choice of the efficient flexural stiffness of the ribbon-profiles is also proposed.
Feasibility Study of Robust Optimization to Reduce Dose Delivery Uncertainty by Potential Applicator Displacements for a Cervix Brachytherapy
Authors: Jo Byungdu , Park Kyeongyun , Shin Dongho , Lim Young Kyung , Jeong Jong Hwi , Lee Se Byeong , Kim Hee-Joung , Kim Haksoo
Published: March 2021

Brachytherapy is an important technique to increase the overall survival of cervical cancer patients. However, a possible shift of the applicators in relation to the target and organs at risk may occur between imaging and treatment. Without daily adaptive brachytherapy planning, these applicator displacements can lead to a significant change in dose distribution. In order to resolve it, a robust optimization method had been developed using a genetic algorithm combined with a median absolute deviation as a robustness evaluation function. The resulting robustness plans from our strategy might be worth considering according to the GEC-ESTRO guidelines. From the point of view of dose delivery uncertainty from applicator displacement, the robust optimization may be considered with caution in a single-plan approach for High Dose Rate brachytherapy treatment planning and should be confirmed by a more thorough investigation.
Biogenic Nanoparticles: Synthesis, Characterisation and Applications
Authors: Mughal Bilal , Zaidi Syed Zohaib Javaid , Zhang Xunli , Hassan Sammer Ul
Published: March 2021

Nanotechnology plays a big part in our modern daily lives, ranging from the biomedical sector to the energy sector. There are different physicochemical and biological methods to synthesise nanoparticles towards multiple applications. Biogenic production of nanoparticles through the utilisation of microorganisms provides great advantages over other techniques and is increasingly being explored. This review examines the process of the biogenic synthesis of nanoparticles mediated by microorganisms such as bacteria, fungi and algae, and their applications. Microorganisms offer a disparate environment for nanoparticle synthesis. Optimum production and minimum time to obtain the desired size and shape, to improve the stability of nanoparticles and to optimise specific microorganisms for specific applications are the challenges to address, however. Numerous applications of biogenic nanoparticles in medicine, environment, drug delivery and biochemical sensors are discussed.
Considerations and Technical Pitfalls in the Employment of the MTT Assay to Evaluate Photosensitizers for Photodynamic Therapy
Authors: Carreño Edith Alejandra , Alberto Anael Viana Pinto , de Souza Cristina Alves Magalhães , de Mello Heber Lopes , Henriques-Pons Andrea , Anastacio Alves Luiz
Published: March 2021

Photodynamic therapy (PDT) combines light, a photosensitizing chemical substance, and molecular oxygen to elicit cell death and is employed in the treatment of a variety of diseases, including cancer. The development of PDT treatment strategies requires in vitro assays to develop new photosensitizers. One such assay is the MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide developed in 1983 and widely used in PDT studies. Despite the exponential growth in the number of publications, a uniform MTT protocol for use in the PDT area is lacking. Herein, we list and standardize the conditions to evaluate the photosensitizer methylene blue (MB) in glioblastoma and neuroblastoma cell lines. In addition, we review technical pitfalls and identify several variables that must be taken into consideration in order to provide accurate results with MTT. We conclude that for each cell line we must have a dose-response curve using the MTT assay and good controls for the standardization. Additionally, the optimal values of the time and cell density must be in the linear range of the curve to avoid errors. We describe all relevant points and outline the best normalization techniques to observe the differences between treatments.
Aeroacoustic Sound Source Characterization of the Human Voice Production-Perturbed Convective Wave Equation
Authors: Schoder Stefan , Maurerlehner Paul , Wurzinger Andreas , Hauser Alexander , Falk Sebastian , Kniesburges Stefan , Döllinger Michael , Kaltenbacher Manfred
Published: March 2021

The flow-induced sound sources of human voice production are investigated based on a validated voice model. This analysis is performed using a hybrid aeroacoustic workflow based on the perturbed convective wave equation. In the first step, the validated 3D incompressible turbulent flow simulation is computed by the finite volume method using STARCCM+. In a second step, the aeroacoustic sources are evaluated and studied in detail. The formulation of the sound sources is compared to the simplification (neglecting the convective sources) systematically using time-domain and Fourier-space analysis. Additionally, the wave equation is solved with the finite element solver openCFS to obtain the 3D sound field in the acoustic far-field. During the detailed effect analysis, the far-field sound spectra are compared quantitatively, and the flow-induced sound sources are visualized within the larynx. In this contribution, it is shown that the convective part of the sources dominates locally near the vocal folds (VFs) while the local time derivative of the incompressible pressure is distributed in the whole supra-glottal area. Although the maximum amplitude of the time derivative is lower, the integral contribution dominates the sound spectrum. As a by-product of the detailed perturbed convective wave equation source study, we show that the convective source term can be neglected since it only reduces the validation error by 0.6%. Neglecting the convective part reduces the algorithmic complexity of the aeroacoustic source computation of the perturbed convective wave equation and the stored flow data. From the source visualization, we learned how the VF motion transforms into specific characteristics of the aeroacoustic sources. We found that if the VFs are fully closing, the aeroacoustic source terms yield the highest dynamical range. If the VFs are not fully closing, VFs motion does not provide as much source energy to the flow-induced sound sources as in the case of a healthy voice. As a consequence of not fully closing VFs, the cyclic pulsating velocity jet is not cut off entirely and therefore turbulent structures are permanently present inside the supraglottal region. These turbulent structures increase the broadband component of the voice signal, which supports research results of previous studies regarding glottis closure and insufficient voice production.
Air Pollution in Moscow Megacity: Data Fusion of the Chemical Transport Model and Observational Network
Authors: Ponomarev Nikolai , Yushkov Vladislav , Elansky Nikolai
Published: March 2021

Comparisons of observational data obtained at the Moscow Ecological Monitoring network (MEM) with numerical simulations using a chemical transformation and transport model (SILAM—System for Integrated modeLling of Atmospheric coMposition) showed that the errors in determining the gaseous pollutant concentrations in the urban atmosphere have a more complex structure than those assumed under the conventional algorithms of data assimilation. These errors are statistically nonstationary; they show a pronounced diurnal cycle and a significant lifetime. The statistical features of errors in numerical calculations also depend upon the type of pollutants, i.e., the chemical reactions in which they participate. Our analysis showed that the simulation errors are not small: the ratios of calculated and measured concentrations (even for daily averages at all measuring stations) may vary in a wide range. For the chemically active pollutants, the intradiurnal error variations may reach 100%. The diurnal cycle of such errors was found to vary according to seasons (in our case, summer and winter). The analysis of statistical properties of the errors, including their temporal and spatial variability, allows one to correct and adequately forecast the air pollution in the metropolis area at lead times up to three days in advance.
Sources of Formaldehyde in Bountiful, Utah
Authors: Bhardwaj Nitish , Kelsch Ariel , Eatough Delbert J. , Thalman Ryan , Daher Nancy , Kelly Kerry , Jaramillo Isabel Cristina , Hansen Jaron C.
Published: March 2021

The U.S Environmental Protection Agency’s National Air Toxics Trends Stations Network has been measuring the concentration of hazardous air pollutants (HAPs) including formaldehyde (HCHO) since 2003. Bountiful, Utah (USA) has served as one of the urban monitoring sites since the network was established. Starting in 2013, the mean concentration of HCHO measured in Bountiful, Utah exceeded the non-cancer risk threshold and the 1 in 1 million cancer risk threshold. In addition, the measured concentrations were more than double those found at surrounding locations in Utah. A Positive Matrix Factorization (PMF) analysis using PMF-EPA v5 was performed using historical data (2004–2017) to better understand the sources of formaldehyde in the region. The historical data set included samples that were collected every sixth day on a 24 h basis. Beginning in February 2019 an eight-week air sampling campaign was initiated to measure formaldehyde on a two-hour averaged basis. In addition, the measurements of O3, NO, NO2, benzene, toluene, ethylbenzene, and xylenes (BTEX) were also collected. Corresponding back-trajectory wind calculations for selected time periods were calculated to aid in the understanding of the effects of BTEX emission sources and formaldehyde formation. The results indicate that the principal formaldehyde sources are associated with biomass burning and the conversion of biogenic emissions into HCHO. Back-trajectory wind analysis of low (≤3 ppbv) and high (23.8–32.5 ppbv) HCHO cases show a clear dominance of high HCHO originating in trajectories that come from the southwest and pass over the area of the oil refineries and industrial sources in the north Salt Lake City area.
Development of an Electron-Atom Compton Scattering Apparatus Using a Picosecond Pulsed Electron Gun
Authors: Tachibana Yuichi , Onitsuka Yuuki , Yamazaki Masakazu , Takahashi Masahiko
Published: March 2021

An apparatus has been developed for electron-atom Compton scattering experiments that can employ a pulsed laser and a picosecond pulsed electron beam in a pump-and-probe scheme. The design and technical details of the apparatus are described. Furthermore, experimental results on the Xe atom in its ground state are presented to illustrate the performance of the pulsed electron gun and the detection and spectrometric capabilities for scattered electrons. The scope of future application is also discussed, involving real-time measurement of intramolecular force acting on each constituent atom with different mass numbers, in a transient, evolving system during a molecular reaction.
Defining the Role of Attention in Hierarchical Auditory Processing
Authors: Price Caitlin N. , Moncrieff Deborah
Published: March 2021

Communication in noise is a complex process requiring efficient neural encoding throughout the entire auditory pathway as well as contributions from higher-order cognitive processes (i.e., attention) to extract speech cues for perception. Thus, identifying effective clinical interventions for individuals with speech-in-noise deficits relies on the disentanglement of bottom-up (sensory) and top-down (cognitive) factors to appropriately determine the area of deficit; yet, how attention may interact with early encoding of sensory inputs remains unclear. For decades, attentional theorists have attempted to address this question with cleverly designed behavioral studies, but the neural processes and interactions underlying attention’s role in speech perception remain unresolved. While anatomical and electrophysiological studies have investigated the neurological structures contributing to attentional processes and revealed relevant brain–behavior relationships, recent electrophysiological techniques (i.e., simultaneous recording of brainstem and cortical responses) may provide novel insight regarding the relationship between early sensory processing and top-down attentional influences. In this article, we review relevant theories that guide our present understanding of attentional processes, discuss current electrophysiological evidence of attentional involvement in auditory processing across subcortical and cortical levels, and propose areas for future study that will inform the development of more targeted and effective clinical interventions for individuals with speech-in-noise deficits.
Impact of Test Conditions While Screening Lithium-Ion Batteries for Capacity Degradation in Low Earth Orbit CubeSat Space Applications
Authors: Cook Riley , Swan Lukas , Plucknett Kevin
Published: March 2021

A wide variety of commercial cylindrical lithium-ion batteries are available for use in nanosatellites (CubeSats) that cycle in low Earth orbit (LEO). This space application differs greatly from the conditions used to create the manufacturer datasheets that CubeSat teams rely on to screen cell types and estimate performance lifetimes. To address this, we experimentally test three LIB cell types using a representative LEO CubeSat power profile in three progressively complex test representations of LEO. The first is “standardized” condition (101 kPa-abs, 20 °C), which uses only a power cycler; the second adds a thermal chamber for “low temperature” condition (101 kPa-abs, 10 °C); and the third adds a vacuum chamber for “LEO” condition (0.2 kPa-abs, 10 °C). Results indicate that general “standardized” and “low temperature” conditions do not yield representative results to what would occur in LEO. Coincidentally, the “LEO” condition gives similar capacity degradation results as manufacturer datasheets. This was an unexpected finding, but suggests that CubeSat teams use full experimental thermal-vacuum testing or default to the manufacturer datasheet performance estimates during the lithium-ion cell screening and selection process. The use of a partial representation of the LEO condition is not recommended.
Molecular Assay Development to Monitor the Kinetics of Viable Populations of Two Biocontrol Agents, Bacillus subtilis QST 713 and Gliocladium catenulatum J1446, in the Phyllosphere of Lettuce Leaves
Authors: Tut Gurkan , Magan Naresh , Brain Philip , Xu Xiangming
Published: March 2021

Optimising the use of biocontrol agents (BCAs) requires the temporal tracking of viable populations in the crop phyllosphere to ensure that effective control can be achieved. No sensitive systems for quantifying viable populations of commercially available BCAs, such as Bacillus subtilis and Gliocladium catenulatum, in the phyllosphere of crop plants are available. The objective of this study was to develop a method to quantify viable populations of these two BCAs in the crop phyllosphere. A molecular tool based on propidium monoazide (PMA) (PMAxx™-qPCR) capable of quantifying viable populations of these two BCAs was developed. Samples were treated with PMAxx™ (12.5–100 μM), followed by 15 min incubation, exposure to a 800 W halogen light for 30 min, DNA extraction, and quantification using qPCR. This provided a platform for using the PMAxx™-qPCR technique for both BCAs to differentiate viable from dead cells. The maximum number of dead cells blocked, based on the DNA, was 3.44 log10 for B. subtilis and 5.75 log10 for G. catenulatum. Validation studies showed that this allowed accurate quantification of viable cells. This method provided effective quantification of the temporal changes in viable populations of the BCAs in commercial formulations on lettuce leaves in polytunnel and glasshouse production systems.
Lumacaftor and Matrine: Possible Therapeutic Combination to Counteract the Inflammatory Process in Cystic Fibrosis
Authors: Pecoraro Michela , Franceschelli Silvia , Pascale Maria
Published: March 2021

Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.
Ex Vivo Generation and Characterization of Human Hyaline and Elastic Cartilaginous Microtissues for Tissue Engineering Applications
Authors: Sánchez-Porras David , Durand-Herrera Daniel , Paes Ana B. , Chato-Astrain Jesús , Verplancke Rik , Vanfleteren Jan , Sánchez-López José Darío , García-García Óscar Darío , Campos Fernando , Carriel Víctor
Published: March 2021

Considering the high prevalence of cartilage-associated pathologies, low self-repair capacity and limitations of current repair techniques, tissue engineering (TE) strategies have emerged as a promising alternative in this field. Three-dimensional culture techniques have gained attention in recent years, showing their ability to provide the most biomimetic environment for the cells under culture conditions, enabling the cells to fabricate natural, 3D functional microtissues (MTs). In this sense, the aim of this study was to generate, characterize and compare scaffold-free human hyaline and elastic cartilage-derived MTs (HC-MTs and EC-MTs, respectively) under expansion (EM) and chondrogenic media (CM). MTs were generated by using agarose microchips and evaluated ex vivo for 28 days. The MTs generated were subjected to morphometric assessment and cell viability, metabolic activity and histological analyses. Results suggest that the use of CM improves the biomimicry of the MTs obtained in terms of morphology, viability and extracellular matrix (ECM) synthesis with respect to the use of EM. Moreover, the overall results indicate a faster and more sensitive response of the EC-derived cells to the use of CM as compared to HC chondrocytes. Finally, future preclinical in vivo studies are still needed to determine the potential clinical usefulness of these novel advanced therapy products.
Less Can Be More: The Hormesis Theory of Stress Adaptation in the Global Biosphere and Its Implications
Authors: Schirrmacher Volker
Published: March 2021

A dose-response relationship to stressors, according to the hormesis theory, is characterized by low-dose stimulation and high-dose inhibition. It is non-linear with a low-dose optimum. Stress responses by cells lead to adapted vitality and fitness. Physical stress can be exerted through heat, radiation, or physical exercise. Chemical stressors include reactive species from oxygen (ROS), nitrogen (RNS), and carbon (RCS), carcinogens, elements, such as lithium (Li) and silicon (Si), and metals, such as silver (Ag), cadmium (Cd), and lead (Pb). Anthropogenic chemicals are agrochemicals (phytotoxins, herbicides), industrial chemicals, and pharmaceuticals. Biochemical stress can be exerted through toxins, medical drugs (e.g., cytostatics, psychopharmaceuticals, non-steroidal inhibitors of inflammation), and through fasting (dietary restriction). Key-lock interactions between enzymes and substrates, antigens and antibodies, antigen-presenting cells, and cognate T cells are the basics of biology, biochemistry, and immunology. Their rules do not obey linear dose-response relationships. The review provides examples of biologic stressors: oncolytic viruses (e.g., immuno-virotherapy of cancer) and hormones (e.g., melatonin, stress hormones). Molecular mechanisms of cellular stress adaptation involve the protein quality control system (PQS) and homeostasis of proteasome, endoplasmic reticulum, and mitochondria. Important components are transcription factors (e.g., Nrf2), micro-RNAs, heat shock proteins, ionic calcium, and enzymes (e.g., glutathion redox enzymes, DNA methyltransferases, and DNA repair enzymes). Cellular growth control, intercellular communication, and resistance to stress from microbial infections involve growth factors, cytokines, chemokines, interferons, and their respective receptors. The effects of hormesis during evolution are multifarious: cell protection and survival, evolutionary flexibility, and epigenetic memory. According to the hormesis theory, this is true for the entire biosphere, e.g., archaia, bacteria, fungi, plants, and the animal kingdoms.
An Optimized and Standardized Rapid Flow Cytometry Functional Method for Heparin-Induced Thrombocytopenia
Authors: Runser Anne , Schaning Caroline , Allemand Frédéric , Amiral Jean
Published: March 2021

Heparin-induced thrombocytopenia (HIT) is a thrombocytopenia caused by heparin and mediated by an atypical immune mechanism leading to a paradoxical high thrombotic risk, associated with severe morbidity or death. The diagnosis of HIT combines a clinical scoring of pretest probability and laboratory testing. First-line routine tests are antigen binding assays detecting specific antibodies. The most sensitive of these tests have a high HIT-negative predictive value enabling HIT diagnosis to be ruled out when negative. However, HIT-positive predictive value is low, and a functional assay evaluating the pathogenicity of the antibodies should be performed to exclude false-positive results. In contrast to screening assays, functional assays are highly specific but technically challenging, and are thus performed in referral laboratories, where platelet activation is detected using radioactive serotonin (serotonin release assay, SRA) or visually (heparin-induced platelet activation, HIPA). Flow cytometry is a possible alternative. It is, however, currently not widely used, mostly because of the lack of standardization of the published assays. This article describes and discusses the standardization of a HIT flow cytometry assay (HIT-FCA) method, which subsequently led to the development and commercialization of a CE-marked assay (HIT Confirm®, Emosis, France) as a suitable rapid HIT functional test.
Antitumor Effects of Ursolic Acid through Mediating the Inhibition of STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer Cells
Authors: Kang Dong Young , Sp Nipin , Lee Jin-Moo , Jang Kyoung-Jin
Published: March 2021

Targeted therapy based on natural compounds is one of the best approaches against non-small cell lung cancer. Ursolic acid (UA), a pentacyclic triterpenoid derived from medicinal herbs, has anticancer activity. Studies on the molecular mechanism underlying UA’s anticancer activity are ongoing. Here, we demonstrated UA’s anticancer activity and the underlying signaling mechanisms. We used Western blotting and real-time quantitative polymerase chain reaction for molecular signaling analysis. We also used in vitro angiogenesis, wound healing, and invasion assays to study UA’s anticancer activity. In addition, we used tumorsphere formation and chromatin immunoprecipitation assays for binding studies. The results showed that UA inhibited the proliferation of A549 and H460 cells in a concentration-dependent manner. UA exerted anticancer effects by inducing G0/G1 cell cycle arrest and apoptosis. It also inhibited tumor angiogenesis, migration, invasion, and tumorsphere formation. The molecular mechanism underlying UA activity involves UA’s binding to epidermal growth factor receptor (EGFR), reducing the level of phospho-EGFR, and thus inhibiting the downstream JAK2/STAT3 pathway. Furthermore, UA reduced the expressions of vascular endothelial growth factor (VEGF), metalloproteinases (MMPs) and programmed death ligand-1 (PD-L1), as well as the formation of STAT3/MMP2 and STAT3/PD-L1 complexes. Altogether, UA exhibits anticancer activities by inhibiting MMP2 and PD-L1 expression through EGFR/JAK2/STAT3 signaling.
The Effect of Small Molecule Pharmacological Agents on the Triterpenoid Saponin Induced Endolysosomal Escape of Saporin and a Saporin-Based Immunotoxin in Target Human Lymphoma Cells
Authors: Wensley Harrison J. , Smith Wendy S. , Holmes Suzanne E. , Flavell Sopsamorn U. , Flavell David J.
Published: March 2021

Triterpenoid saponins augment the cytotoxicity of saporin based immunotoxins. It is postulated that this results from a saponin-mediated increase in the endolysosomal escape of the toxin to the cytosol, but this remains to be confirmed. To address this issue, we used a number of pharmacological inhibitors of endocytic processes as probes to investigate the role played by saponin in the endolysosomal escape of fluorescently labeled saporin and a saporin based immunotoxin targeted against CD38 on human lymphoma and leukemia cell lines. Endolysosomal escape of the toxin was measured by flow cytometric pulse shape analysis. These results were compared to the effects of the various inhibitors on the saponin-mediated augmentation of toxin and immunotoxin cytotoxicity. Inhibitors of clathrin-mediated endocytosis, micropinocytosis, and endosomal acidification abrogated the saponin-induced increase in the endolysosomal escape of the toxin into the cytosol, suggesting that these processes may be involved in the internalization of saponin to the same endolysosomal vesicle as the toxin. Alternatively, these processes may play a direct role in the mechanism by which saponin promotes toxin escape from the endolysosomal compartment to the cytosol. Correlation with the effects of these inhibitors on the augmentation of cytotoxicity provides additional evidence that endolysosomal escape is involved in driving augmentation.
Signal Amplification in an Optical and Dielectric Biosensor Employing Liquid Crystal-Photopolymer Composite as the Sensing Medium
Authors: Shaban Hassanein , Yen Shih-Chun , Lee Mon-Juan , Lee Wei
Published: March 2021

An optical and dielectric biosensor based on a liquid crystal (LC)–photopolymer composite was established in this study for the detection and quantitation of bovine serum albumin (BSA). When the nematic LC E7 was doped with 4-wt.% NOA65, a photo-curable prepolymer, and photopolymerized by UV irradiation at 20 mW/cm2 for 300 s, the limit of detection determined by image analysis of the LC optical texture and dielectric spectroscopic measurements was 3400 and 88 pg/mL for BSA, respectively, which were lower than those detected with E7 alone (10 μg/mL BSA). The photopolymerized NOA65, but not the prepolymer prior to UV exposure, contributed to the enhanced optical signal, and UV irradiation of pristine E7 in the absence of NOA65 had no effect on the optical texture. The effective tilt angle θ, calculated from the real-part dielectric constant ε’, decreased with increasing BSA concentration, providing strong evidence for the correlation of photopolymerized NOA65 to the intensified disruption in the vertically oriented LC molecules to enhance the optical and dielectric signals of BSA. The optical and dielectric anisotropy of LCs and the photo-curable dopant facilitate novel quantitative and signal amplification approaches to potential development of LC-based biosensors.
Biosensors for Biogenic Amines: A Review
Authors: Vasconcelos Helena , Coelho Luís C. C. , Matias Ana , Saraiva Cristina , Jorge Pedro A. S. , de Almeida José M. M. M.
Published: March 2021

Biogenic amines (BAs) are well-known biomolecules, mostly for their toxic and carcinogenic effects. Commonly, they are used as an indicator of quality preservation in food and beverages since their presence in higher concentrations is associated with poor quality. With respect to BA’s metabolic pathways, time plays a crucial factor in their formation. They are mainly formed by microbial decarboxylation of amino acids, which is closely related to food deterioration, therefore, making them unfit for human consumption. Pathogenic microorganisms grow in food without any noticeable change in odor, appearance, or taste, thus, they can reach toxic concentrations. The present review provides an overview of the most recent literature on BAs with special emphasis on food matrixes, including a description of the typical BA assay formats, along with its general structure, according to the biorecognition elements used (enzymes, nucleic acids, whole cells, and antibodies). The extensive and significant amount of research that has been done to the investigation of biorecognition elements, transducers, and their integration in biosensors, over the years has been reviewed.
A Nation-Wide, Multi-Center Study on the Quality of Life of ALS Patients in Germany
Authors: Peseschkian Tara , Cordts Isabell , Günther René , Stolte Benjamin , Zeller Daniel , Schröter Carsten , Weyen Ute , Regensburger Martin , Wolf Joachim , Schneider Ilka , Hermann Andreas , Metelmann Moritz , Kohl Zacharias , Linker Ralf A. , Koch Jan Christoph , Büchner Boriana , Weiland Ulrike , Schönfelder Erik , Heinrich Felix , Osmanovic Alma , Klopstock Thomas , Dorst Johannes , Ludolph Albert C. , Boentert Matthias , Hagenacker Tim , Deschauer Marcus , Lingor Paul , Petri Susanne , Schreiber-Katz Olivia
Published: March 2021

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology
Authors: Avazzadeh Sahar , Baena Jara Maria , Keighron Cameron , Feller-Sanchez Yajaira , Quinlan Leo R.
Published: March 2021

Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.
Breastfeeding during COVID-19: A Narrative Review of the Psychological Impact on Mothers
Authors: Pacheco Francisca , Sobral Mónica , Guiomar Raquel , de la Torre-Luque Alejandro , Caparros-Gonzalez Rafael A. , Ganho-Ávila Ana
Published: March 2021

The COVID-19 pandemic has altered the normal course of life, with measures to reduce the virus spread impacting motherhood expectations and, in particular, breastfeeding practices. This study aimed to review evidence regarding the impact of COVID-19 on breastfeeding plans and how these relate to women’s psychological outcomes. Searches were conducted on PubMed and Web of Science for studies in English, Spanish, and Portuguese between January 2020 and January 2021. All study designs and pre-prints were considered. Twelve studies were included. Reports suggest that COVID-19 impacts differently on breastfeeding plans, which in turn leads to distinctive mental health outcomes. Positive breastfeeding experiences have been observed when mothers perceive that they have more time for motherhood, which may be associated with better mental health outcomes. Negative breastfeeding experiences have been observed when mothers are separated from their newborns, when mothers struggle with breastfeeding, or when mothers perceive decreased family and professional support, which seems to be associated with worse mental health outcomes. These preliminary results highlight the need for further research into the association between COVID-19, breastfeeding expectations, and maternal mental health. Filling this gap will foster the development of guidelines and interventions to better support mothers experiencing the obstacles of COVID-19 pandemic.
Mechanical Characterization of Iroko Wood Using Small Specimens
Authors: Cunha Carlos , Tenório Marina , Lima Daniel F. , Rebouças Arthur , Neves Luís C. , Branco Jorge M.
Published: March 2021

Despite their favorable physical and mechanical properties for structural use, tropical woods, such as Iroko (Milicia excelsa), present knowledge gaps to be filled mainly about their mechanical characterization, which currently limit their use or result in under- or overdimensioned structural elements. Visual classification, one of the most used methods for characterizing wood, is inaccurate in the case of Iroko due to the wide variety of geographical locations in which this species can be found. In addition, mechanical characterization using test pieces with structural dimensions leads to high and impractical costs. In this context, this study aims to verify the mechanical properties of Iroko (imported from the Republic of the Congo) from small size specimens, a process that is currently standardized only for softwoods, and to verify the correlation of different properties through bending properties and ultrasound tests. Prior to the bending tests, the speed of propagation of ultrasonic waves was measured using the direct method. The results obtained show a good correlation between density and bending properties and the velocity of propagation of ultrasonic waves.
Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review
Authors: Corso Giovanni , Corso Federica , Bellerba Federica , Carneiro Patrícia , Seixas Susana , Cioffi Antonio , La Vecchia Carlo , Magnoni Francesca , Bonanni Bernardo , Veronesi Paolo , Gandini Sara , Figueiredo Joana
Published: March 2021

Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.
Rho Family GTPases in Cancer
Authors: Dharmawardhane Suranganie
Published: March 2021

This Special Issue containing seminal contributions from international experts highlights the current understanding of Rho GTPases in cancer, with an emphasis on recognizing their central importance as critical targets for cancer therapy and for chemosensitization of current therapeutic strategies [...]
Switching off Cancer: Is There a Role for Epigenetics?
Authors: Avery-Kiejda Kelly A.
Published: March 2021

Epigenetics is the study of heritable changes in gene expression that do not involve any change in DNA sequence and include methylation, histone modifications, and altered miRNA or lncRNA expression [...]
Regulation of Long Non-Coding RNAs by Plant Secondary Metabolites: A Novel Anticancer Therapeutic Approach
Authors: Kalhori Mohammad Reza , Khodayari Hamid , Khodayari Saeed , Vesovic Miko , Jackson Gloria , Farzaei Mohammad Hosein , Bishayee Anupam
Published: March 2021

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play an essential role in various cellular activities, such as differentiation, proliferation, and apoptosis. Dysregulation of lncRNAs serves a fundamental role in the progression and initiation of various diseases, including cancer. Precision medicine is a suitable and optimal treatment method for cancer so that based on each patient’s genetic content, a specific treatment or drug is prescribed. The rapid advancement of science and technology in recent years has led to many successes in this particular treatment. Phytochemicals are a group of natural compounds extracted from fruits, vegetables, and plants. Through the downregulation of oncogenic lncRNAs or upregulation of tumor suppressor lncRNAs, these bioactive compounds can inhibit metastasis, proliferation, invasion, migration, and cancer cells. These natural products can be a novel and alternative strategy for cancer treatment and improve tumor cells’ sensitivity to standard adjuvant therapies. This review will discuss the antineoplastic effects of bioactive plant secondary metabolites (phytochemicals) via regulation of expression of lncRNAs in various human cancers and their potential for the treatment and prevention of human cancers.
Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL
Authors: Guarente Valerio , Sportoletti Paolo
Published: March 2021

Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment.
Therapeutic Implications of the Immunoscore in Patients with Colorectal Cancer
Authors: El Sissy Carine , Kirilovsky Amos , Zeitoun Guy , Marliot Florence , Haicheur Nacilla , Lagorce-Pagès Christine , Galon Jérôme , Pagès Franck
Published: March 2021

Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the “Immunoscore” (IS), to accurately prognosticate colon cancers beyond the TNM-system. The standardization process included not only the IS conceptualization, development, fine-tuning, and validation by a large international consortium, but also a demonstration of the robustness and reproducibility across the world and testing of international norms and their effects on the IS. This is the first step of a major change of paradigm that now perceives cancer as the result of contradicting driving forces, i.e., the tumor expansion and the immune response, interacting dynamically and influencing the prognosis and the response to therapies. This prompted us to evaluate and evidence the capacity of the tumor immune status, as reflected by the IS, to accurately predict chemotherapy responses in an international, randomized cohort study of colon cancer. Moreover, we developed a derived IS performed on initial diagnostic biopsies (ISB) to assess response levels to neoadjuvant therapies. In rectal cancer, ISB was positively correlated with the degree of histologic response to neoadjuvant chemoradiotherapy and identified - alone and even more accurately if combined with clinical data- patients eligible for a noninvasive strategy. Based on these results, we are currently setting up an international cohort for confirmation. The potential role of IS with immunotherapies must be anticipated.