bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-Dependent Performance of a Multi-Hop Software Defined Network
Authors: Czachórski Tadeusz , Gelenbe Erol , Kuaban Godlove Suila , Marek Dariusz
Published: March 2021

It has been recently observed that Software Defined Networks (SDN) can change the paths of different connections in the network at a relatively frequent pace to improve the overall network performance, including delay and packet loss, or to respond to other needs such as security. These changes mean that a network that SDN controls will seldom operate in steady state; rather, the network may often be in transient mode, especially when the network is heavily loaded and path changes are critically important. Hence, we propose a transient analysis of such networks to better understand how frequent changes in paths and the switches’ workloads may affect multi-hop networks’ performance. Since conventional queueing models are difficult to solve for transient behaviour and simulations take excessive computation time due to the need for statistical accuracy, we use a diffusion approximation to study a multi-hop network controlled by SDN. The results show that network optimization should consider the transient effects of SDN and that transients need to be included in the design of algorithms for SDN controllers that optimize network performance.
Genetic Optimization of a Manipulator: Comparison between Straight, Rounded, and Curved Mechanism Links
Authors: Pastor Robert , Bobovský Zdenko , Huczala Daniel , Grushko Stefan
Published: March 2021

There are several ubiquitous kinematic structures that are used in industrial robots, with the most prominent being a six-axis angular structure. However, researchers are experimenting with task-based mechanism synthesis that could provide higher efficiency with custom optimized manipulators. Many studies have focused on finding the most efficient optimization algorithm for task-based robot manipulators. These manipulators, however, are usually optimized from simple modular joints and links, without exploring more elaborate modules. Here, we show that link modules defined by small numbers of parameters have better performance than more complicated ones. We compare four different manipulator link types, namely basic predefined links with fixed dimensions, straight links that can be optimized for different lengths, rounded links, and links with a curvature defined by a Hermite spline. Manipulators are then built from these modules using a genetic algorithm and are optimized for three different tasks. The results demonstrate that manipulators built from simple links not only converge faster, which is expected given the fewer optimized parameters, but also converge on lower cost values.
Spectral Analysis of Electroencephalographic Data in Serious Games
Authors: Babusiak Branko , Hostovecky Marian , Smondrk Maros , Huraj Ladislav
Published: March 2021

In this paper, we describe an investigation of brain activity while playing a serious game (SG). A SG is focused on improving logical thinking, specifically on cognitive training of students in the field of basic logic gates, and we summarize SG description, design, and development. A method based on various signal processing techniques for evaluating electroencephalographic (EEG) data was implemented in the MATLAB. This assessment was based on the analysis of the spectrogram of particular brain activity. Changes in brain activity power at a characteristic frequency band during the gameplay were calculated from the spectrogram. The EEG of 21 respondents was measured. Based on the results, the respondents can be divided into three groups according to specific EEG activity changes during the gameplay compared to a relaxed state. The beta/alpha ratio, an indicator of brain employment to a mental task, was increased during gameplay in 18 of the 21 subjects. Our results reflected the sex of respondents, time of the game and the indicator, and whether the game was successfully completed.
A Review of Power Management Integrated Circuits for Ultrasound-Based Energy Harvesting in Implantable Medical Devices
Authors: Ballo Andrea , Bottaro Michele , Grasso Alfio Dario
Published: March 2021

This paper aims to review the recent architectures of power management units for ultrasound-based energy harvesting, while focusing on battery-less implantable medical devices. In such systems, energy sustainability is based on piezoelectric devices and a power management circuit, which represents a key building block since it maximizes the power extracted from the piezoelectric devices and delivers it to the other building blocks of the implanted device. Since the power budget is strongly constrained by the dimension of the piezoelectric energy harvester, complexity of topologies have been increased bit by bit in order to achieve improved power efficiency also in difficult operative conditions. With this in mind, the introduced work consists of a comprehensive presentation of the main blocks of a generic power management unit for ultrasound-based energy harvesting and its operative principles, a review of the prior art and a comparative study of the performance achieved by the considered solutions. Finally, design guidelines are provided, allowing the designer to choose the best topology according to the given design specifications and technology adopted.
Capsule Network Improved Multi-Head Attention for Word Sense Disambiguation
Authors: Cheng Jinfeng , Tong Weiqin , Yan Weian
Published: March 2021

Word sense disambiguation (WSD) is one of the core problems in natural language processing (NLP), which is to map an ambiguous word to its correct meaning in a specific context. There has been a lively interest in incorporating sense definition (gloss) into neural networks in recent studies, which makes great contribution to improving the performance of WSD. However, disambiguating polysemes of rare senses is still hard. In this paper, while taking gloss into consideration, we further improve the performance of the WSD system from the perspective of semantic representation. We encode the context and sense glosses of the target polysemy independently using encoders with the same structure. To obtain a better presentation in each encoder, we leverage the capsule network to capture different important information contained in multi-head attention. We finally choose the gloss representation closest to the context representation of the target word as its correct sense. We do experiments on English all-words WSD task. Experimental results show that our method achieves good performance, especially having an inspiring effect on disambiguating words of rare senses.
Removal of Cyanotoxins–Microcystins from Water by Filtration through Granulated Composites of Bentonite with Micelles of the Cation Octadecyltrimethyl Ammonium (ODTMA)
Authors: Sukenik Assaf , Viner-Mozzini Yehudit , Mizrahi Daniel , Tamam Imri , Benitez Ana R. , Nir Shlomo
Published: March 2021

Cyanobacteria and their toxins present potential hazards to consumers of water from lakes, reservoirs and rivers; thus, their removal via water treatment is essential. Previously, we demonstrated that nanocomposites of octadecyltrimethyl ammonium (ODTMA) complexed with clay could efficiently remove cyanobacteria and their toxins from laboratory cultures and lake water. In this study, we determined the capacity of ODTMA nanocomposites to remove cyanotoxins, namely microcystins (MCs), from water to below 1 µg/L via filtration. This capacity was 1500 mg MC-LR per Kg of nanocomposite. Similar capacities were estimated for the removal of other MC congeners (MC-WR, MC-3aspWR and MC-YR), whereas substantially lower capacities were recorded for more positively charged MC congeners, such as MC-RR and MC-3aspRR. Filtration results were simulated with a filtration model, which considers convection and adsorption/desorption of one to several toxins. Model calculations for the removal of MC-LR, under a variety of situations, fitted well with all the experimentally measured values and also estimated the co-removal of several MC congeners. In agreement with model predictions, results demonstrated that in the presence of MC-WR, the emerging concentrations of MC-RR congeners eventually exceed their solution values. In conclusion, granulated nanocomposites of ODTMA–bentonite can be applied for the removal of microcystins from drinking water.
From data Processing to Knowledge Processing: Working with Operational Schemas by Autopoietic Machines
Authors: Burgin Mark , Mikkilineni Rao
Published: March 2021

Knowledge processing is an important feature of intelligence in general and artificial intelligence in particular. To develop computing systems working with knowledge, it is necessary to elaborate the means of working with knowledge representations (as opposed to data), because knowledge is an abstract structure. There are different forms of knowledge representations derived from data. One of the basic forms is called a schema, which can belong to one of three classes: operational, descriptive, and representation schemas. The goal of this paper is the development of theoretical and practical tools for processing operational schemas. To achieve this goal, we use schema representations elaborated in the mathematical theory of schemas and use structural machines as a powerful theoretical tool for modeling parallel and concurrent computational processes. We describe the schema of autopoietic machines as physical realizations of structural machines. An autopoietic machine is a technical system capable of regenerating, reproducing, and maintaining itself by production, transformation, and destruction of its components and the networks of processes downstream contained in them. We present the theory and practice of designing and implementing autopoietic machines as information processing structures integrating both symbolic computing and neural networks. Autopoietic machines use knowledge structures containing the behavioral evolution of the system and its interactions with the environment to maintain stability by counteracting fluctuations.
Circadian Misalignment and Metabolic Disorders: A Story of Twisted Clocks
Authors: Woller Aurore , Gonze Didier
Published: March 2021

Biological clocks are cell-autonomous oscillators that can be entrained by periodic environmental cues. This allows organisms to anticipate predictable daily environmental changes and, thereby, to partition physiological processes into appropriate phases with respect to these changing external conditions. Nowadays our 24/7 society challenges this delicate equilibrium. Indeed, many studies suggest that perturbations such as chronic jet lag, ill-timed eating patterns, or shift work increase the susceptibility to cardiometabolic disorders, diabetes, and cancers. However the underlying mechanisms are still poorly understood. A deeper understanding of this complex, dynamic system requires a global holistic approach for which mathematical modeling can be highly beneficial. In this review, we summarize several experimental works pertaining to the effect of adverse conditions on clock gene expression and on physiology, and we show how computational models can bring interesting insights into the links between circadian misalignment and metabolic diseases.
Effect of Tibolone on Bone Mineral Density in Postmenopausal Women: Systematic Review and Meta-Analysis
Authors: Castrejón-Delgado Lizett , Castelán-Martínez Osvaldo D. , Clark Patricia , Garduño-Espinosa Juan , Mendoza-Núñez Víctor Manuel , Sánchez-Rodríguez Martha A.
Published: March 2021

Low bone mineral density (BMD) on postmenopausal women causes bone fragility and fracture risk. Tibolone seems to prevent bone loss. Therefore, this systematic review with meta-analysis synthesizes the tibolone effect on BMD percent change in lumbar spine (LS), femoral neck (FN), and total hip (TH) in postmenopausal women. Controlled trials that provided tibolone evidence on the efficacy of tibolone in preventing loss of BMD were included. Regarding the included studies, a pooled mean difference (MD) with 95% confidence intervals (95%CI) was estimated to determine the BMD percentage change. Eleven studies were identified and eight were included in the quantitative analysis. Tibolone at a dose of 2.5 mg increased BMD compared with non-active controls at 24 months in LS (MD 4.87%, 95%CI: 4.16–5.57, and MD 7.35%, 95%CI: 2.68–12.01); and FN (MD 4.85%, 95%CI: 1.55–8.15, and 4.21%, 95%CI: 2.99–5.42), with Hologic and Lunar scanners, respectively. No difference was observed when tibolone 2.5 mg dose was compared with estrogen therapy (ET) at 24 months, LS (MD −0.58%, 95%CI: −3.77–2.60), FN (MD −0.29%, 95%CI: −1.37–0.79), and TH (MD −0.12%, 95%CI: −2.28–2.53). Therefore, tibolone increases BMD in LS and FN compared to non-active controls, and there was no showed difference with ET.
TRIM32: A Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis
Authors: Bawa Simranjot , Piccirillo Rosanna , Geisbrecht Erika R.
Published: March 2021

Human tripartite motif family of proteins 32 (TRIM32) is a ubiquitous multifunctional protein that has demonstrated roles in differentiation, muscle physiology and regeneration, and tumor suppression. Mutations in TRIM32 result in two clinically diverse diseases. A mutation in the B-box domain gives rise to Bardet–Biedl syndrome (BBS), a disease whose clinical presentation shares no muscle pathology, while mutations in the NHL (NCL-1, HT2A, LIN-41) repeats of TRIM32 causes limb-girdle muscular dystrophy type 2H (LGMD2H). TRIM32 also functions as a tumor suppressor, but paradoxically is overexpressed in certain types of cancer. Recent evidence supports a role for TRIM32 in glycolytic-mediated cell growth, thus providing a possible mechanism for TRIM32 in the accumulation of cellular biomass during regeneration and tumorigenesis, including in vitro and in vivo approaches, to understand the broad spectrum of TRIM32 functions. A special emphasis is placed on the utility of the Drosophila model, a unique system to study glycolysis and anabolic pathways that contribute to the growth and homeostasis of both normal and tumor tissues.
Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
Authors: Delfino Danila , Mori Giulia , Rivetti Claudio , Grigoletto Antonella , Bizzotto Gloria , Cavozzi Cristian , Malatesta Marco , Cavazzini Davide , Pasut Gianfranco , Percudani Riccardo
Published: March 2021

In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease.
Mechanisms of Transthyretin Inhibition of IAPP Amyloid Formation
Authors: Wasana Jayaweera Sanduni , Surano Solmaz , Pettersson Nina , Oskarsson Elvira , Lettius Lovisa , Gharibyan Anna , Anan Intissar , Olofsson Anders
Published: March 2021

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.
Natural Extracts to Augment Energy Expenditure as a Complementary Approach to Tackle Obesity and Associated Metabolic Alterations
Authors: Reguero Marina , Gómez de Cedrón Marta , Reglero Guillermo , Quintela José Carlos , Ramírez de Molina Ana
Published: March 2021

Obesity is the epidemic of the 21st century. In developing countries, the prevalence of obesity continues to rise, and obesity is occurring at younger ages. Obesity and associated metabolic stress disrupt the whole-body physiology. Adipocytes are critical components of the systemic metabolic control, functioning as an endocrine organ. The enlarged adipocytes during obesity recruit macrophages promoting chronic inflammation and insulin resistance. Together with the genetic susceptibility (single nucleotide polymorphisms, SNP) and metabolic alterations at the molecular level, it has been highlighted that key modifiable risk factors, such as those related to lifestyle, contribute to the development of obesity. In this scenario, urgent therapeutic options are needed, including not only pharmacotherapy but also nutrients, bioactive compounds, and natural extracts to reverse the metabolic alterations associated with obesity. Herein, we first summarize the main targetable processes to tackle obesity, including activation of thermogenesis in brown adipose tissue (BAT) and in white adipose tissue (WAT-browning), and the promotion of energy expenditure and/or fatty acid oxidation (FAO) in muscles. Then, we perform a screening of 20 natural extracts (EFSA approved) to determine their potential in the activation of FAO and/or thermogenesis, as well as the increase in respiratory capacity. By means of innovative technologies, such as the study of their effects on cell bioenergetics (Seahorse bioanalyzer), we end up with the selection of four extracts with potential application to ameliorate the deleterious effects of obesity and the chronic associated inflammation.
Medial Temporal Lobe Involvement in Human Prion Diseases: Implications for the Study of Focal Non Prion Neurodegenerative Pathology
Authors: Rábano Alberto , Guerrero Márquez Carmen , Juste Ramón A. , Geijo María V. , Calero Miguel
Published: March 2021

Human prion and non-prion neurodegenerative diseases share pathogenic mechanisms and neuropathological features. The lesion profile of a particular entity results from specific involvement of vulnerable neuron populations and connectivity circuits by a pathogenic protein isoform with strain-like properties. The lesion profile of the medial temporal lobe (MTL) was studied in postmortem tissue of 143 patients with human prion disease (HPD) including sporadic, genetic, and acquired forms. Most cases (90%) were classified according to PrPres type and/or PRNP codon 129 status, in addition to a full neuropathological profile. Mixed histotypes represented 29.4% of total sporadic Creutzfeldt-Jakob disease (sCJD) cases. An intensity score of involvement including spongiosis and astrogliosis was determined for the amygdala, presubiculum, subiculum, entorhinal cortex, CA1 to CA4 sectors of the hippocampal cortex, and dentate gyrus. Connectivity hubs within the MTL presented the highest scores. Diverse lesion profiles were obtained for different types and subtypes of HPD. Impact of mixed PrPres types on the MTL lesion profile was higher for sCJDMV2K cases than in other histotypes. Differences between MTL profiles was globally consistent with current evidence on specific strains in HPD. These results may be relevant for the analysis of possible strain effects in focal non-prion neurodegenerative conditions limited to the MTL.
Soluble JAM-C Ectodomain Serves as the Niche for Adipose-Derived Stromal/Stem Cells
Authors: Yamazaki Morio , Sugimoto Kotaro , Mabuchi Yo , Yamashita Rina , Ichikawa-Tomikawa Naoki , Kaneko Tetsuharu , Akazawa Chihiro , Hasegawa Hiroshi , Imura Tetsuya , Chiba Hideki
Published: March 2021

Junctional adhesion molecules (JAMs) are expressed in diverse types of stem and progenitor cells, but their physiological significance has yet to be established. Here, we report that JAMs exhibit a novel mode of interaction and biological activity in adipose-derived stromal/stem cells (ADSCs). Among the JAM family members, JAM-B and JAM-C were concentrated along the cell membranes of mouse ADSCs. JAM-C but not JAM-B was broadly distributed in the interstitial spaces of mouse adipose tissue. Interestingly, the JAM-C ectodomain was cleaved and secreted as a soluble form (sJAM-C) in vitro and in vivo, leading to deposition in the fat interstitial tissue. When ADSCs were grown in culture plates coated with sJAM-C, cell adhesion, cell proliferation and the expression of five mesenchymal stem cell markers, Cd44, Cd105, Cd140a, Cd166 and Sca-1, were significantly elevated. Moreover, immunoprecipitation assay showed that sJAM-C formed a complex with JAM-B. Using CRISPR/Cas9-based genome editing, we also demonstrated that sJAM-C was coupled with JAM-B to stimulate ADSC adhesion and maintenance. Together, these findings provide insight into the unique function of sJAM-C in ADSCs. We propose that JAMs contribute not only to cell–cell adhesion, but also to cell–matrix adhesion, by excising their ectodomain and functioning as a niche-like microenvironment for stem and progenitor cells.
Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions
Authors: Matsuishi Yujiro , Mathis Bryan J. , Shimojo Nobutake , Subrina Jesmin , Okubo Nobuko , Inoue Yoshiaki
Published: March 2021

Since December 2019, the SARS-CoV-2 (COVID-19) pandemic has transfixed the medical world. COVID-19 symptoms vary from mild to severe and underlying chronic conditions such as pulmonary/cardiovascular disease and diabetes induce excessive inflammatory responses to COVID-19 and these underlying chronic diseases are mediated by endothelial dysfunction. Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID-19 patients, but coagulation induced by excessive inflammation, thrombosis, and disseminated intravascular coagulation (DIC) also induce death by multiple-organ dysfunction syndrome. These associations imply that maintaining endothelial integrity is crucial for favorable prognoses with COVID-19 and therapeutic intervention to support this may be beneficial. Here, we summarize the extent of heart injuries, ischemic stroke and hemorrhage, acute kidney injury, and liver injury caused by immune-mediated endothelial dysfunction that result in the phenomenon of multi-organ dysfunction seen in COVID-19 patients. Moreover, the potential therapeutic effect of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors that improve endothelial dysfunction as well as the bradykinin storm are discussed.
Role of RGMc as a Neogenin Ligand in Follicular Development in the Ovary
Authors: Kim Yu Jin , Park YoungJoon , Park Yeo Reum , Kim Young Sang , Lee Hye Ran , Lee Sang Jin , Kim Myung Joo , Kwack KyuBum , Ko Jung Jae , Lee Jae Ho
Published: March 2021

There is currently no cure for infertility in women with a poor ovarian response (POR). Neogenin is reported to be abundantly expressed in the ovary; however, its role in mammalian follicular development is unclear and its ligand and signaling pathway remain uncertain. We systematically investigated the role of neogenin and the ligand repulsive guidance molecule c (RGMc) during follicular development. We treated hyperstimulated mouse ovaries with RGMc and analyzed follicular development. Furthermore, we investigated clusters of up/downregulated genes in RGMc-treated ovaries using whole-transcriptome next-generation sequencing (NGS). In addition, we investigated whether expression of up/downregulated factors identified by NGS was also altered in cumulus cells (CCs) of patients with a POR. The number of oocytes was 40% higher in RGMc-treated ovaries than in control ovaries. NGS data indicated that prostaglandin D2 (PGD2) was involved in the RGMc signaling pathway during follicular development. RGMc treatment significantly elevated the PGD2 level in culture medium of CCs obtained from patients with a POR. Our results demonstrate that RGMc as neogenin ligand promotes follicular development in ovaries via the PGD2 signaling pathway. Therefore, it may be possible to use RGMc for ovarian stimulation in patients with a POR.
Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model
Authors: Sintsova Oksana , Gladkikh Irina , Monastyrnaya Margarita , Tabakmakher Valentin , Yurchenko Ekaterina , Menchinskaya Ekaterina , Pislyagin Evgeny , Andreev Yaroslav , Kozlov Sergey , Peigneur Steve , Tytgat Jan , Aminin Dmitry , Kozlovskaya Emma , Leychenko Elena
Published: March 2021

Kunitz-type peptides from venomous animals have been known to inhibit different proteinases and also to modulate ion channels and receptors, demonstrating analgesic, anti-inflammatory, anti-histamine and many other biological activities. At present, there is evidence of their neuroprotective effects. We have studied eight Kunitz-type peptides of the sea anemone Heteractis crispa to find molecules with cytoprotective activity in the 6-OHDA-induced neurotoxicity model on neuroblastoma Neuro-2a cells. It has been shown that only five peptides significantly increase the viability of neuronal cells treated with 6-OHDA. The TRPV1 channel blocker, HCRG21, has revealed the neuroprotective effect that could be indirect evidence of TRPV1 involvement in the disorders associated with neurodegeneration. The pre-incubation of Neuro-2a cells with HCRG21 followed by 6-OHDA treatment has resulted in a prominent reduction in ROS production compared the untreated cells. It is possible that the observed effect is due to the ability of the peptide act as an efficient free-radical scavenger. One more leader peptide, InhVJ, has shown a neuroprotective activity and has been studied at concentrations of 0.01–10.0 µM. The target of InhVJ is still unknown, but it was the best of all eight homologous peptides in an absolute cell viability increment on 38% of the control in the 6-OHDA-induced neurotoxicity model. The targets of the other three active peptides remain unknown.
Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure
Authors: Lu Cheng-Wei , Lin Tzu-Yu , Pan Tai-Long , Wang Pei-Wen , Chiu Kuan-Ming , Lee Ming-Yi , Wang Su-Jane
Published: March 2021

Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from the medicinal herb Centella asiatica, has already been demonstrated; however, its role in epilepsy-related cognitive deficits is yet to be determined. In this study, we evaluated the effects of asiatic acid on cognitive deficits in rats with kainic acid (KA)-induced seizure and explored the potential mechanisms underlying these effects. Our results revealed that asiatic acid administrated intraperitoneally 30 min prior to KA (15 mg/kg) injection ameliorated seizures and significantly improved KA-induced memory deficits, as demonstrated by the results of the Morris water maze test. In addition, asiatic acid ameliorated neuronal damage, inhibited calpain activation, and increased protein kinase B (AKT) activation in the hippocampus of KA-treated rats. Asiatic acid also increased the levels of synaptic proteins and the number of synaptic vesicles as well as attenuated mitochondrial morphology damage in the hippocampus of KA-treated rats. Furthermore, proteomic and Western blot analyses of hippocampal synaptosomes revealed that asiatic acid reversed KA-induced changes in mitochondria function-associated proteins, including lipoamide dehydrogenase, glutamate dehydrogenase 1 (GLUD1), ATP synthase (ATP5A), and mitochondrial deacetylase sirtuin-3 (SIRT3). Our data suggest that asiatic acid can prevent seizures and improve cognitive impairment in KA-treated rats by reducing hippocampal neuronal damage through the inhibition of calpain activation and the elevation of activated AKT, coupled with an increase in synaptic and mitochondrial function.
The Relationship between Occupationally Exposed Arsenic, Cadmium and Lead and Brain Bioelectrical Activity—A Visual and Brainstem Auditory Evoked Potentials Study
Authors: Waliszewska-Prosół Marta , Ejma Maria , Gać Paweł , Szymańska-Chabowska Anna , Koszewicz Magdalena , Budrewicz Sławomir , Mazur Grzegorz , Bilińska Małgorzata , Poręba Rafał
Published: March 2021

The aim of this study was to evaluate the parameters of visual and brainstem auditory evoked potentials in patients occupationally exposed to arsenic, cadmium and lead. The study group comprised 41 copper smelter and refinery workers (average age: 51.27) with occupational exposure to arsenic, cadmium and lead. The control group consisted of 36 healthy volunteers (35 men and 1 woman, aged 27–66, average age: 51.08). Neurological examination, brain imaging, and visual and brainstem auditory evoked potentials were performed, and the relationship between blood Cd, Pb concentration (Cd-B, Pb-B), blood zinc protoporphyrin (ZnPP), and urine As concentration (As-U) were assessed. In the workers, exceedances of allowable biological concentrations were observed, with the urinary concentration of arsenic being 5.2%, the cadmium and lead in blood being 1.3%, while the case of ZnPP was 2.6%. The mean P100, relative P100, and N145 visual evoked potential (VEP) latencies were significantly longer in exposed workers than in the controls. The mean wave III and V brainstem auditory evoked potential (BAEP) latency and the mean wave III–V and I–V interpeak latencies were longer, and the I and V amplitude was lower in the workers than the controls. In summary, occupational exposure to As, Cd, and Pb is associated with prolonged latency and reduced evoked potential amplitude, but As-U, Pb-B, Cd-B, and ZnPP concentrations are not linearly related to potential components. The analysis of evoked potentials may be a useful method of assessment of the central nervous system in patients with occupational exposure to heavy metals.
Anxiety towards Statistics and Its Relationship with Students’ Attitudes and Learning Approach
Authors: Peiró-Signes Ángel , Trull Oscar , Segarra-Oña Marival , García-Díaz J. Carlos
Published: March 2021

Many university students have difficulties when facing statistics related tasks, leading to an increase in their levels of anxiety and poor performance. Researchers have identified negative attitudes towards statistics, which have been shaped through students’ secondary education experience, as a major driver for their failure. In this study we want to uncover the causal recipes of attitudes leading to high and low levels of anxiety in secondary education students, and the role that the learning approach plays in these relationships. We used fuzzy sets comparative qualitative analysis (fsQCA) in a sample of 325 students surveyed on the multifactorial scale of attitudes toward statistics (MSATS) and the revised two factor study process questionnaire (R-SPQ-2F). The results indicate that, respectively, a high or a low level of self-confidence is the most important and a sufficient condition by itself for achieving a low or a high level of anxiety, while the learning approaches and other attitudes are only present in other causal combinations that represent a small number of cases.
Molecular Signature of Small Cell Lung Cancer after Treatment Failure: The MCM Complex as Therapeutic Target
Authors: Misono Shunsuke , Mizuno Keiko , Suetsugu Takayuki , Tanigawa Kengo , Nohata Nijiro , Uchida Akifumi , Sanada Hiroki , Okada Reona , Moriya Shogo , Inoue Hiromasa , Seki Naohiko
Published: March 2021

Small cell lung cancer (SCLC) is a highly aggressive cancer, and patients who become refractory to first-line treatment have a poor prognosis. The development of effective treatment regimens is urgently needed. In this study, we identified a gene expression signature of SCLC after treatment failure using SCLC clinical specimens (GEO accession number: GSE162102). A total of 1,136 genes were significantly upregulated in SCLC tissues. These upregulated genes were subjected to KEGG pathway analysis, and “cell cycle”, “Fanconi anemia”, “alcoholism”, “systemic lupus erythematosus”, “oocyte meiosis”, “homologous recombination”, “DNA replication”, and “p53 signaling” were identified as the enriched pathways among the genes. We focused on the cell cycle pathway and investigated the clinical significance of four genes associated with this pathway: minichromosome maintenance (MCM) 2, MCM4, MCM6, and MCM7. The overexpression of these MCM genes was confirmed in SCLC clinical specimens. Knockdown assays using siRNAs targeting each of these four MCM genes showed significant attenuation of cancer cell proliferation. Moreover, siRNA-mediated knockdown of each MCM gene enhanced the cisplatin sensitivity of SCLC cells. Our SCLC molecular signature based on SCLC clinical specimens after treatment failure will provide useful information to identify novel molecular targets for this disease.
Linking Serine/Glycine Metabolism to Radiotherapy Resistance
Authors: Sánchez-Castillo Anaís , Vooijs Marc , Kampen Kim R.
Published: March 2021

The activation of de novo serine/glycine biosynthesis in a subset of tumors has been described as a major contributor to tumor pathogenesis, poor outcome, and treatment resistance. Amplifications and mutations of de novo serine/glycine biosynthesis enzymes can trigger pathway activation; however, a large group of cancers displays serine/glycine pathway overexpression induced by oncogenic drivers and unknown regulatory mechanisms. A better understanding of the regulatory network of de novo serine/glycine biosynthesis activation in cancer might be essential to unveil opportunities to target tumor heterogeneity and therapy resistance. In the current review, we describe how the activation of de novo serine/glycine biosynthesis in cancer is linked to treatment resistance and its implications in the clinic. To our knowledge, only a few studies have identified this pathway as metabolic reprogramming of cancer cells in response to radiation therapy. We propose an important contribution of de novo serine/glycine biosynthesis pathway activation to radioresistance by being involved in cancer cell viability and proliferation, maintenance of cancer stem cells (CSCs), and redox homeostasis under hypoxia and nutrient-deprived conditions. Current approaches for inhibition of the de novo serine/glycine biosynthesis pathway provide new opportunities for therapeutic intervention, which in combination with radiotherapy might be a promising strategy for tumor control and ultimately eradication. Further research is needed to gain molecular and mechanistic insight into the activation of this pathway in response to radiation therapy and to design sophisticated stratification methods to select patients that might benefit from serine/glycine metabolism-targeted therapies in combination with radiotherapy.
Homology-Based Image Processing for Automatic Classification of Histopathological Images of Lung Tissue
Authors: Nishio Mizuho , Nishio Mari , Jimbo Naoe , Nakane Kazuaki
Published: March 2021

The purpose of this study was to develop a computer-aided diagnosis (CAD) system for automatic classification of histopathological images of lung tissues. Two datasets (private and public datasets) were obtained and used for developing and validating CAD. The private dataset consists of 94 histopathological images that were obtained for the following five categories: normal, emphysema, atypical adenomatous hyperplasia, lepidic pattern of adenocarcinoma, and invasive adenocarcinoma. The public dataset consists of 15,000 histopathological images that were obtained for the following three categories: lung adenocarcinoma, lung squamous cell carcinoma, and benign lung tissue. These images were automatically classified using machine learning and two types of image feature extraction: conventional texture analysis (TA) and homology-based image processing (HI). Multiscale analysis was used in the image feature extraction, after which automatic classification was performed using the image features and eight machine learning algorithms. The multicategory accuracy of our CAD system was evaluated in the two datasets. In both the public and private datasets, the CAD system with HI was better than that with TA. It was possible to build an accurate CAD system for lung tissues. HI was more useful for the CAD systems than TA.
Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma
Authors: Kumar Ashwini , Adhikari Sadiksha , Kankainen Matti , Heckman Caroline A.
Published: March 2021

Linked-read sequencing was developed to aid the detection of large structural variants (SVs) from short-read sequencing efforts. We performed a systematic evaluation to determine if linked-read exome sequencing provides more comprehensive and clinically relevant information than whole-exome sequencing (WES) when applied to the same set of multiple myeloma patient samples. We report that linked-read sequencing detected a higher number of SVs (n = 18,455) than WES (n = 4065). However, linked-read predictions were dominated by inversions (92.4%), leading to poor detection of other types of SVs. In contrast, WES detected 56.3% deletions, 32.6% insertions, 6.7% translocations, 3.3% duplications and 1.2% inversions. Surprisingly, the quantitative performance assessment suggested a higher performance for WES (AUC = 0.791) compared to linked-read sequencing (AUC = 0.766) for detecting clinically validated cytogenetic alterations. We also found that linked-read sequencing detected more short variants (n = 704) compared to WES (n = 109). WES detected somatic mutations in all MM-related genes while linked-read sequencing failed to detect certain mutations. The comparison of somatic mutations detected using linked-read, WES and RNA-seq revealed that WES and RNA-seq detected more mutations than linked-read sequencing. These data indicate that WES outperforms and is more efficient than linked-read sequencing for detecting clinically relevant SVs and MM-specific short variants.
Maternal and Neonatal Outcome after the Use of G-CSF for Cancer Treatment during Pregnancy
Authors: Berends Claudia , Maggen Charlotte , Lok Christianne A. R. , van Gerwen Mathilde , Boere Ingrid A. , Wolters Vera E. R. A. , Van Calsteren Kristel , Segers Heidi , van den Heuvel-Eibrink Marry M. , Painter Rebecca C. , Gziri Mina Mhallem , Amant Frédéric
Published: March 2021

Data on the use of Granulocyte colony-stimulating factor (G-CSF) in pregnant cancer patients are scarce. The International Network of Cancer, Infertility and Pregnancy (INCIP) reviewed data of pregnant patients treated with chemotherapy and G-CSF, and their offspring. Among 2083 registered patients, 42 pregnant patients received G-CSF for the following indications: recent chemotherapy induced febrile neutropenia (5; 12%), dose dense chemotherapy (28, 67%), poly chemotherapy (7, 17%), or prevention of neutropenia at delivery (2; 5%). Among 24 women receiving dose dense chemotherapy, three (13%) patients recovered from asymptomatic neutropenia within 5 days. One patient developed pancytopenia following polychemotherapy after which the pregnancy was complicated by chorioamnionitis and intrauterine death. Nineteen singleton livebirths (49%) were born preterm. Sixteen neonates (41%) were admitted to the Neonatal Intensive care Unit (NICU). No neonatal neutropenia occurred. Two neonates had congenital malformations. Out of 21 children in follow-up, there were four children with a motor development delay and two premature infants had a delay in cognitive development. In conclusion, the rate of maternal and neonatal complications are similar to those described in (pregnant) women treated with chemotherapy. Due to small numbers and limited follow-up, rare or delayed effects among offspring exposed to G-CSF in utero cannot be ruled out yet.
Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix
Authors: Takayanagi Daisuke , Hirose Sou , Kuno Ikumi , Asami Yuka , Murakami Naoya , Matsuda Maiko , Shimada Yoko , Sunami Kuniko , Komatsu Masaaki , Hamamoto Ryuji , Kato Mayumi Kobayashi , Matsumoto Koji , Kohno Takashi , Kato Tomoyasu , Shiraishi Kouya , Yoshida Hiroshi
Published: March 2021

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.
Catalytic Transformation of Renewables (Olefin, Bio-Sourced, et al.)
Authors: Dimitratos Nikolaos , Albonetti Stefania , Tabanelli Tommaso
Published: March 2021

The objective of this Special Issue is to provide new diverse contributions that can demonstrate recent applications in biomass transformation using heterogeneous catalysts [...]
Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
Authors: Pantazopoulou Vasiliki , Jeannot Pauline , Rosberg Rebecca , Berg Tracy J. , Pietras Alexander
Published: March 2021

Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.
Fluorogenic Aptasensors with Small Molecules
Authors: Lee Eun-Song , Lee Jeong Min , Kim Hea-Jin , Kim Young-Pil
Published: March 2021

Aptamers are single-stranded DNA or RNA molecules that can be identified through an iterative in vitro selection–amplification process. Among them, fluorogenic aptamers in response to small molecules have been of great interest in biosensing and bioimaging due to their rapid fluorescence turn-on signals with high target specificity and low background noise. In this review, we report recent advances in fluorogenic aptasensors and their applications to in vitro diagnosis and cellular imaging. These aptasensors modulated by small molecules have been implemented in different modalities that include duplex or molecular beacon-type aptasensors, aptazymes, and fluorogen-activating aptamer reporters. We highlight the working principles, target molecules, modifications, and performance characteristics of fluorogenic aptasensors, and discuss their potential roles in the field of biosensor and bioimaging with future directions and challenges.
The Effect of Music on aEEG Cyclicity in Preterm Neonates
Authors: Giordano Vito , Goeral Katharina , Schrage-Leitner Leslie , Berger Angelika , Olischar Monika
Published: March 2021

Several methods can be used in the neonatal intensive care unit (NICU) to reduce stress and optimize the quality of life during this period of hospitalization. Among these, music could play an important role. We investigated the effect of different kinds of music therapies on the brain activity of very preterm infants using amplitude-integrated EEG. Sixty-four patients were included and randomly assigned to three different groups: live music group, recorded music group, and control group. In both intervention groups, music was started after the appearance of the first quiet-sleep phase, with a subsequent duration of 20 min. Changes between the first and second quiet-sleep epochs were analyzed using the amplitude-integrated EEG. When looking at single parameters of the amplitude-integrated EEG trace, no differences could be found between the groups when comparing their first and second quiet-sleep phase regarding the parameters of change from baseline, quality of the quiet-sleep epoch, and duration. However, when looking at the total cyclicity score of the second quiet-sleep phase, a difference between both intervention groups and the control group could be found (live music therapy vs. control, p = 0.003; recorded music therapy vs. control, p = 0.006). Improvement within the first and second quiet-sleep epochs were detected in both music groups, but not in the control group. We concluded that our study added evidence of the beneficial effect of music on the amplitude-integrated EEG activity in preterm infants.