bluuebunny/crossref_metadata_2025 huggingface dataset:
Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A
Authors: Guadagni Stefano , Farina Antonietta Rosella , Cappabianca Lucia Annamaria , Sebastiano Michela , Maccarone Rita , Zelli Veronica , Clementi Marco , Chiominto Alessandro , Bruera Gemma , Ricevuto Enrico , Fiorentini Giammaria , Sarti Donatella , Mackay Andrew Reay
Published: November 2020

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.
Emerging Role for Linear and Circular Spermine Oxidase RNAs in Skeletal Muscle Physiopathology
Authors: Reinoso-Sánchez Jonathan Fernando , Baroli Giulia , Duranti Guglielmo , Scaricamazza Silvia , Sabatini Stefania , Valle Cristiana , Morlando Mariangela , Casero Robert Anthony Casero , Bozzoni Irene , Mariottini Paolo , Ceci Roberta , Cervelli Manuela
Published: November 2020

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1G93A and hFUS+/+, characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy.
Report of Five Years of Experience in Neonatal Screening for Mucopolysaccharidosis Type I and Review of the Literature
Authors: Gragnaniello Vincenza , Gueraldi Daniela , Rubert Laura , Manzoni Francesca , Cazzorla Chiara , Giuliani Antonella , Polo Giulia , Salviati Leonardo , Burlina Alberto
Published: November 2020

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disease, with neurological and visceral involvement, in which early diagnosis through newborn screening (NBS) and early treatment can improve outcomes. We present our first 5 years of experience with laboratory and clinical management of NBS for MPS I. Since 2015, we have screened 160,011 newborns by measuring α-L-iduronidase (IDUA) activity and, since 2019, glycosaminoglycans (GAGs) in dried blood spot (DBS) as a second-tier test. Positive screening patients were referred to our clinic for confirmatory clinical and molecular testing. We found two patients affected by MPS I (incidence of 1:80,005). Before the introduction of second-tier testing, we found a high rate of false-positives due to pseudodeficiency. With GAG analysis in DBS as a second-tier test, no false-positive newborns were referred to our clinic. The confirmed patients were early treated with enzyme replacement therapy and bone-marrow transplantation. For both, the clinical outcome of the disease is in the normal range. Our experience confirms that NBS for MPS I is feasible and effective, along with the need to include GAG assay as a second-tier test. Follow-up of the two positive cases identified confirms the importance of early diagnosis through NBS and early treatment to improve the outcome of these patients.
Investigation of Combining Logitboost(M5P) under Active Learning Classification Tasks
Authors: Kazllarof Vangjel , Karlos Stamatis , Kotsiantis Sotiris
Published: November 2020

Active learning is the category of partially supervised algorithms that is differentiated by its strategy to combine both the predictive ability of a base learner and the human knowledge so as to exploit adequately the existence of unlabeled data. Its ambition is to compose powerful learning algorithms which otherwise would be based only on insufficient labelled samples. Since the latter kind of information could raise important monetization costs and time obstacles, the human contribution should be seriously restricted compared with the former. For this reason, we investigate the use of the Logitboost wrapper classifier, a popular variant of ensemble algorithms which adopts the technique of boosting along with a regression base learner based on Model trees into 3 different active learning query strategies. We study its efficiency against 10 separate learners under a well-described active learning framework over 91 datasets which have been split to binary and multi-class problems. We also included one typical Logitboost variant with a separate internal regressor for discriminating the benefits of adopting a more accurate regression tree than one-node trees, while we examined the efficacy of one hyperparameter of the proposed algorithm. Since the application of the boosting technique may provide overall less biased predictions, we assume that the proposed algorithm, named as Logitboost(M5P), could provide both accurate and robust decisions under active learning scenarios that would be beneficial on real-life weakly supervised classification tasks. Its smoother weighting stage over the misclassified cases during training as well as the accurate behavior of M5P are the main factors that lead towards this performance. Proper statistical comparisons over the metric of classification accuracy verify our assumptions, while adoption of M5P instead of weak decision trees was proven to be more competitive for the majority of the examined problems. We present our results through appropriate summarization approaches and explanatory visualizations, commenting our results per case.
Physiological Analysis and Transcriptome Analysis of Asian Honey Bee (Apis cerana cerana) in Response to Sublethal Neonicotinoid Imidacloprid
Authors: Gao Jing , Jin San-Sheng , He Yan , Luo Jin-Hong , Xu Chun-Qin , Wu Yan-Yan , Hou Chun-Shen , Wang Qiang , Diao Qing-Yun
Published: November 2020

Asian honey bee (Apis cerana) is the most important Chinese indigenous species, while its toxicological characteristic against neonicotinoids is poorly known. Here, we combined physiological experiments with a genome-wide transcriptome analysis to understand the molecular basis of genetic variation that responds to sublethal imidacloprid at different exposure durations in A. cerana. We found that LC5 dose of imidacloprid had a negative impact on climbing ability and sucrose responsiveness in A. cerana. When bees were fed with LC5 dose of imidacloprid, the enzyme activities of P450 and CarE were decreased, while the GSTs activity was not influenced by the pesticide exposure. The dynamic transcriptomic profiles of A. cerana workers exposed to LC5 dose of imidacloprid for 1 h, 8 h, and 16 h were obtained by high-throughput RNA-sequencing. We performed the expression patterns of differentially expressed genes (DEGs) through trend analysis, and conducted the gene ontology analysis and KEGG pathway enrichment analysis with DEGs in up- and down-regulated pattern profiles. We observed that more genes involved in metabolism, catalytic activity, and structural molecule activity are down-regulated; while more up-regulated genes were enriched in terms associated with response to stimulus, transporter activity, and signal transducer activity. Additionally, genes related to the phenylalanine metabolism pathway, FoxO signaling pathway, and mTOR signaling pathway as indicated in the KEGG analysis were significantly up-related in the exposed bees. Our findings provide a comprehensive understanding of Asian honey bee in response to neonicotinoids sublethal toxicity, and could be used to further investigate the complex molecular mechanisms in Asian honey bee under pesticide stress.
Experimental Scours by Impinging Twin-Propeller Jets at Quay Wall
Authors: Cui Yonggang , Lam Wei Haur , Ong Zhi Chao , Ling Lloyd , Siow Chee Loon , Robinson Desmond , Hamill Gerard
Published: November 2020

Experiments were conducted to investigate the seabed scour holes due to the interaction between the twin-propeller jet and quay wall. Vertical quay wall was modelled by using a polyvinyl chloride (PVC) plastic plate in a water tank. The relationship between the positions of the propeller and the vertical quay wall was designed according to the actual working conditions of a ship entering and leaving a port. Propeller-to-wall distance and rotational speed were changed to observe the various scour conditions. The scour depth was measured by using an Acoustic Doppler Velocimeter (ADV). Primary scour hole was found within the jet downstream and secondary scour hole occurred beneath of the propeller. Third scour hole was found close to the quay wall due to horseshoe vortices. The maximum scour position of this third scour hole was found at the jet centre near the quay wall. Temporal formation of scour holes can be divided into three stages: axial scour formation, obstructed scour expansion and equilibrium stages. The quantitative relationships for six characteristic parameters of the scour pit were established including the maximum scour depth (εmax,q), maximum scour depth position (Xm,q), maximum scour width (Wm,q), length of main scour pit (XS,q), maximum deposition height (ZD,q), and location of maximum deposition height (XD,q).
Epidemiology and Diagnosis of Mucormycosis: An Update
Authors: Skiada Anna , Pavleas Ioannis , Drogari-Apiranthitou Maria
Published: November 2020

Mucormycosis is an angioinvasive fungal infection, due to fungi of the order Mucorales. Its incidence cannot be measured exactly, since there are few population-based studies, but multiple studies have shown that it is increasing. The prevalence of mucormycosis in India is about 80 times the prevalence in developed countries, being approximately 0.14 cases per 1000 population. Diabetes mellitus is the main underlying disease globally, especially in low and middle-income countries. In developed countries the most common underlying diseases are hematological malignancies and transplantation. Τhe epidemiology of mucormycosis is evolving as new immunomodulating agents are used in the treatment of cancer and autoimmune diseases, and as the modern diagnostic tools lead to the identification of previously uncommon genera/species such as Apophysomyces or Saksenaea complex. In addition, new risk factors are reported from Asia, including post-pulmonary tuberculosis and chronic kidney disease. New emerging species include Rhizopus homothallicus, Thamnostylum lucknowense, Mucor irregularis and Saksenaea erythrospora. Diagnosis of mucormycosis remains challenging. Clinical approach to diagnosis has a low sensitivity and specificity, it helps however in raising suspicion and prompting the initiation of laboratory testing. Histopathology, direct examination and culture remain essential tools, although the molecular methods are improving. The internal transcribed spacer (ITS) region is the most widely sequenced DNA region for fungi and it is recommended as a first-line method for species identification of Mucorales. New molecular platforms are being investigated and new fungal genetic targets are being explored. Molecular-based methods have gained acceptance for confirmation of the infection when applied on tissues. Methods on the detection of Mucorales DNA in blood have shown promising results for earlier and rapid diagnosis and could be used as screening tests in high-risk patients, but have to be validated in clinical studies. More, much needed, rapid methods that do not require invasive procedures, such as serology-based point-of-care, or metabolomics-based breath tests, are being developed and hopefully will be evaluated in the near future.
CoCDaR and mCoCDaR: New Approach for Measurement of Systemic Risk Contributions
Authors: Ding Rui , Uryasev Stan
Published: November 2020

Systemic risk is the risk that the distress of one or more institutions trigger a collapse of the entire financial system. We extend CoVaR (value-at-risk conditioned on an institution) and CoCVaR (conditional value-at-risk conditioned on an institution) systemic risk contribution measures and propose a new CoCDaR (conditional drawdown-at-risk conditioned on an institution) measure based on drawdowns. This new measure accounts for consecutive negative returns of a security, while CoVaR and CoCVaR combine together negative returns from different time periods. For instance, ten 2% consecutive losses resulting in 20% drawdown will be noticed by CoCDaR, while CoVaR and CoCVaR are not sensitive to relatively small one period losses. The proposed measure provides insights for systemic risks under extreme stresses related to drawdowns. CoCDaR and its multivariate version, mCoCDaR, estimate an impact on big cumulative losses of the entire financial system caused by an individual firm’s distress. It can be used for ranking individual systemic risk contributions of financial institutions (banks). CoCDaR and mCoCDaR are computed with CVaR regression of drawdowns. Moreover, mCoCDaR can be used to estimate drawdowns of a security as a function of some other factors. For instance, we show how to perform fund drawdown style classification depending on drawdowns of indices. Case study results, data, and codes are posted on the web.
Economic Advantages of Community Currencies
Authors: Zeller Sarah
Published: November 2020

Community currencies are only sometimes economically advantageous. We focus on seasonal changes in money supply and assume that community currencies stabilize the money supply in a local community. This leads to additional transactions during seasons of insufficient supply of national currency. We hypothesize community currencies are therefore economically advantageous in a surrounding of seasonally insufficient money supply. We test the hypothesis qualitatively with two case studies, the German Chiemgauer and the Kenyan Sarafu Credit. We find community currencies are only economically advantageous in an environment of insufficient liquidity.
Analytical Model for Springback Prediction of CuZn20 Foil Considering Size Effects: Weakening versus Strengthening
Authors: Guan Xin , Ma Zhenwu , Wang Chunju , He Haidong , Zhang Yuanjing , Wang Xinwei , Zhang Weiwei
Published: November 2020

The prediction of springback angle for ultra-thin metallic sheets becomes extremely difficult with the existence of size effects. In this study, size effects on the springback behavior of CuZn20 foils are investigated by experiments and analytical methods. The experimental results reveal that the springback angle first decreases gradually and then increases markedly with the decrease of foil thickness, which cannot be analyzed by current theoretical models. Then, an analytical model based on the Taylor-based nonlocal theory of plasticity is developed, in which the drastic increases of both the proportion of surface grains and the strain gradient are taken into account. Moreover, the influence of strain gradient is modified by the grain-boundary blocking factor. The calculation results show that the springback angle of foils is determined by the intrinsic competition between the decrement angle caused by surface grains and the increment angle caused by the strain gradient. Besides, the relative error of predicted springback angle by the model is less than 15%, which means that the developed model is very useful for improving the quality of micro sheet parts with high accuracy of springback prediction.
Leaching of Carbon Reinforced Concrete—Part 2: Discussion of Evaluation Concepts and Modelling
Authors: Weiler Lia , Vollpracht Anya , Matschei Thomas
Published: November 2020

Possible threats on the environment and human health by the leaching of new building materials and composites in contact to water should be prevented from the outset. It is therefore necessary to assess and ensure their environmental compatibility. For irrigated construction elements this is a challenging task, as there is no general correlation between known testing methods and outdoor emissions. A feasible assessment concept is needed for these conditions. In this work the German assessment method for permanently wet building materials is applied on different carbon reinforced concrete (C3) leaching data. Furthermore, emission prediction approaches of the Dutch building Materials Decree and the software COMLEAM are tested. The established methods are not yet suitable to determine the complex long term outdoor emissions of irrigated C3. In order to achieve realistic results in time saving testing methods and to define reasonable release limits, it is necessary to determine and verify the relevant influencing parameters on leaching through intermittent water contact. This research works out leaching patterns and correlations between inorganic substances. It is shown that the input parameters time of exposure, contact time, air temperature, air humidity, runoff and background concentration should be considered to predict the leaching processes from irrigated concrete phenomenologically.
Diamond-Like-Carbon Coated Dies for Electromagnetic Embossing
Authors: Herrmann Marius , Beckschwarte Björn , Hasselbruch Henning , Heidhoff Julian , Schenck Christian , Riemer Oltmann , Mehner Andreas , Kuhfuss Bernd
Published: November 2020

Electromagnetic forming is a high-speed process, which features contactless force transmission. Hence, punching operations can be realized with a one-sided die and without a mechanical punch. As the forces act as body forces in the part near the surface, the process is especially convenient for embossing microstructures on thin sheet metals. Nevertheless, the die design is critical concerning wear like adhesion. Several die materials were tested, like aluminum, copper as well as different steel types. For all die materials adhesion phenomena were observed. To prevent such adhesion an a-C:H-PVD (Physical Vapor Deposition)-coating was applied to steel dies (X153CrMoV12) and tested by embossing aluminum sheets (Al99.5). By this enhancement of the die adhesion was prevented. Furthermore, the die surface was structured with tribology-effective patterns that were generated by micro hard milling. The embossing quality was topographically analyzed with respect to different initial surface states of the sheets. It was identified that thicker sheets facilitate better embossing results. Moreover, the initial sheet surface has a decisive influence on the embossing quality, whereby the characteristic of the topography showed different susceptibility on the initial sheet surface state.
Technological Factors That Influence the Mathematics Performance of Secondary School Students
Authors: Gómez-García Melchor , Hossein-Mohand Hassan , Trujillo-Torres Juan Manuel , Hossein-Mohand Hossein , Aznar-Díaz Inmaculada
Published: November 2020

Although the value of information and communication technology (ICT) is positive and its use is widespread, its potential as a teaching tool in mathematics is not optimized and its methodological integration is rare. In addition, the availability of ICT resources in schools is positively associated with the academic success of students, and the availability of ICT resources at home is negatively associated with their success. To determine the relationships among academic performance, uses, and available ICT resources, a total of 2018 secondary school students participated in the present study. The uses and available ICT resources, and the learning of mathematics and ICT, were evaluated using a validated 11-item questionnaire. Statistical analysis reveals that, of the secondary education levels, the lowest results are observed in the third year. A total of 64% of students affirm that they use ICT at home to study mathematics. In addition, 33.61% of the students affirm that they use their mobile phones frequently while studying at home. However, it should be noted that between 23.80% and 28.44% affirm that they dedicate more than 4 h per day to phone calls. Educational level is a predictor of academic performance in mathematics associated with students’ uses of ICT. The scores indicate that the computer is generally used for Internet searches, thus, limiting the use of ICT for educational purposes. Furthermore, there is a difference regarding gender.
Synchronization in Time-Varying and Evolving Complex Networks
Authors: Solís-Perales Gualberto , Zapata José Luis , Obregón-Pulido Guillermo
Published: November 2020

In this contribution, we present the synchronization in dynamical complex networks with varying couplings. We identify two kinds of variations—(i) Non autonomous (Time-varying) couplings: where the coupling strength depends exclusively on time, (ii) Autonomous or Varying couplings (evolution) where the coupling strength depends on the behavior of the interconnected systems. The coupling strength in (i) is exogenous whereas in (ii) the coupling strength is endogenous and is defined by the states of the systems in the nodes. The exponential stability of the synchronization is ensured for the non autonomous couplings, due to the imposition of the coupling strength. Whereas, in the case of evolutionary couplings the exponential stability of the synchronization is not guaranteed for all time, due to the couplings are not controlled or imposed. We present an overview of these features in complex networks and illustrated by means of numerical examples.
A Unifying Numerical Framework for the “Small-Slope” Based Core-Annular Flow Instability Models
Authors: Quevedo Antonio , Fuentes Carlos , Chávez Carlos , González-Sosa Enrique , Mota Carlos
Published: November 2020

The snap-off is an instability phenomenon that takes place during the immiscible two-phase flow in porous media due to competing forces acting on the fluid phases and at the interface between them. Different theoretical approaches have been proposed for the development of mathematical models that describe the dynamics of a fluid/fluid interface in order to analyze the snap-off mechanism. The models studied here are based on the “small-slope” approach and were derived from the mass conservation and other governing equations of two-phase flow at pore scale in circular capillaries for pure and complex interfaces. The models consist of evolution equations; highly nonlinear partial differential equations of fourth order in space and first order in time. Although the structure of the models for each type of interface is similar, different numerical techniques have been employed to solve them. Here, we propose a unifying numerical framework to solve the group of such models. Such a framework is based on the Fourier pseudo-spectral differentiation method which uses the Fast Fourier Transform (FFT) and the inverse FFT (IFFT) algorithms. We compared the solutions obtained with this method to the results reported in the literature in order to validate our framework. In general, acceptable agreements were obtained in the dynamics of the snap-off.
Effect of Temperature-Dependent Bacterial Growth during Milk Protein Fractionation by Means of 0.1 µM Microfiltration on the Length of Possible Production Cycle Times
Authors: Schiffer Simon , Kulozik Ulrich
Published: November 2020

This study determined the maximum possible filtration time per filtration cycle and the cumulated number of operational hours per year as a function of the processing temperature during milk protein fractionation by 0.1 µm microfiltration (MF) of pasteurized skim milk. The main stopping criteria were the microbial count (max. 105 cfu/mL) and the slope of the pH change as a function of filtration time. A membrane system in a feed and bleed configuration with partial recirculation of the retentate was installed, resembling an industrial plants’ operational mode. Filtration temperatures of 10, 14, 16, 20, and 55 °C were investigated to determine the flux, pH, and bacterial count. While the processing time was limited to 420 min at a 55 °C filtration temperature, it could exceed 1440 min at 10 °C. These data can help to minimize the use of cleaning agents or mixing phase losses by reducing the frequency of cleaning cycles, thus maximizing the active production time and reducing the environmental impact.
Removal of Zn(II) in Synthetic Wastewater Using Agricultural Wastes
Authors: Gómez Aguilar Dora Luz , Rodríguez Miranda Juan Pablo , Astudillo Miller María Xóchitl , Maldonado Astudillo Rayma Ireri , Esteban Muñoz Javier Andrés
Published: November 2020

In the present investigation, results obtained from the process of the biosorption of Zn(II) in synthetic wastewaters are presented, using three agricultural wastes (coffee pulp, banana pseudo-stem, and corncob). Firstly, the percentage of lignin and cellulose for each material was determined. Then, using the free software XLSTAT, the waste with the highest removal for this metal was selected and, after this, the optimum pH, kinetics, adsorption isotherm, and point of zero charge (pHpzc) were found. Finally, a comparison with other lignocellulosic materials derived from banana, corn, and coffee crops was carried out. According to the results obtained, coffee pulp was the material that showed a high removal compared to the other two (63.58%), for which the optimum pH was 5.0 units. The kinetic model, which was adjusted to the process of biosorption, was the pseudo second order of Ho and McKay, which in turn presented an isotherm of Langmuir’s linearized model where the maximum adsorption capacity with that waste was 13.53 mg × g−1, obtained with a particle size of 180 µm, contact time of 90 min at 100 RPM, temperature of 25 °C, and pHpzc 3.95 units. Lastly, the authors state that this type of agricultural waste can be used as a green technology in the treatment of wastewater, particularly in the removal of the aforementioned pollutant, in order to fulfill goals 3.9 and 6.9 of the Sustainable Development Goals of the 2030 Agenda; to the level of challenge of the research, the authors propose for the future to carry out the implementation of this type of waste, without chemical modification, in the treatment of wastewater for the removal of the mentioned pollutant in a pilot study with different wastewaters and industries.
A Novel UHPLC-MS Method Targeting Urinary Metabolomic Markers for Autism Spectrum Disorder
Authors: Olesova Dominika , Galba Jaroslav , Piestansky Juraj , Celusakova Hana , Repiska Gabriela , Babinska Katarina , Ostatnikova Daniela , Katina Stanislav , Kovac Andrej
Published: November 2020

Autism spectrum disorder is a heterogeneous neurodevelopmental disease. Currently, no biomarker of this disease is known. Diagnosis is performed through observation, standardized behavioral scales, and interviews with parents. In practice, diagnosis is often delayed to the average age of four years or even more which adversely affects a child’s perspective. A laboratory method allowing to detect the disorder at earlier stages is of a great need, as this could help the patients to start with treatment at a younger age, even prior to the clinical diagnosis. Recent evidence indicates that metabolomic markers should be considered as diagnostic markers, also serving for further differentiation and characterization of different subgroups of the autism spectrum. In this study, we developed an ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry method for the simultaneous determination of six metabolites in human urine. These metabolites, namely methylguanidine, N-acetyl arginine, inosine, indole-3-acetic acid, indoxyl sulfate and xanthurenic acid were selected as potential biomarkers according to prior metabolomic studies. The analysis was carried out by means of reversed-phase liquid chromatography with gradient elution. Separation of the metabolites was performed on a Phenomenex Luna® Omega Polar C18 (100 × 1.0 mm, 1.6 µm) column at a flow rate of 0.15 mL/min with acetonitrile/water 0.1% formic acid aqueous as the mobile phase. The analysis was performed on a group of children with autism spectrum disorder and age-matched controls. In school children, we have detected disturbances in the levels of oxidative stress markers connected to arginine and purine metabolism, namely methylguanidine and N-acetylargine. Also, products of gut bacteria metabolism, namely indoxyl sulfate and indole-3-acetic acid, were found to be elevated in the patients’ group. We can conclude that this newly developed method is fast, sensitive, reliable, and well suited for the quantification of proposed markers.
Genomic and Physiological Properties of a Facultative Methane-Oxidizing Bacterial Strain of Methylocystis sp. from a Wetland
Authors: Jung Gi-Yong , Rhee Sung-Keun , Han Young-Soo , Kim So-Jeong
Published: November 2020

Methane-oxidizing bacteria are crucial players in controlling methane emissions. This study aimed to isolate and characterize a novel wetland methanotroph to reveal its role in the wetland environment based on genomic information. Based on phylogenomic analysis, the isolated strain, designated as B8, is a novel species in the genus Methylocystis. Strain B8 grew in a temperature range of 15 °C to 37 °C (optimum 30–35 °C) and a pH range of 6.5 to 10 (optimum 8.5–9). Methane, methanol, and acetate were used as carbon sources. Hydrogen was produced under oxygen-limited conditions. The assembled genome comprised of 3.39 Mbp and 59.9 mol% G + C content. The genome contained two types of particulate methane monooxygenases (pMMO) for low-affinity methane oxidation (pMMO1) and high-affinity methane oxidation (pMMO2). It was revealed that strain B8 might survive atmospheric methane concentration. Furthermore, the genome had various genes for hydrogenase, nitrogen fixation, polyhydroxybutyrate synthesis, and heavy metal resistance. This metabolic versatility of strain B8 might enable its survival in wetland environments.
Decoding the Genomic Variability among Members of the Bifidobacterium dentium Species
Authors: Lugli Gabriele Andrea , Tarracchini Chiara , Alessandri Giulia , Milani Christian , Mancabelli Leonardo , Turroni Francesca , Neuzil-Bunesova Vera , Ruiz Lorena , Margolles Abelardo , Ventura Marco
Published: November 2020

Members of the Bifidobacterium dentium species are usually identified in the oral cavity of humans and associated with the development of plaque and dental caries. Nevertheless, they have also been detected from fecal samples, highlighting a widespread distribution among mammals. To explore the genetic variability of this species, we isolated and sequenced the genomes of 18 different B. dentium strains collected from fecal samples of several primate species and an Ursus arctos. Thus, we investigated the genomic variability and metabolic abilities of the new B. dentium isolates together with 20 public genome sequences. Comparative genomic analyses provided insights into the vast metabolic repertoire of the species, highlighting 19 glycosyl hydrolases families shared between each analyzed strain. Phylogenetic analysis of the B. dentium taxon, involving 1140 conserved genes, revealed a very close phylogenetic relatedness among members of this species. Furthermore, low genomic variability between strains was also confirmed by an average nucleotide identity analysis showing values higher than 98.2%. Investigating the genetic features of each strain, few putative functional mobile elements were identified. Besides, a consistent occurrence of defense mechanisms such as CRISPR–Cas and restriction–modification systems may be responsible for the high genome synteny identified among members of this taxon.
Structure-Property Relationships of 2D Ga/In Chalcogenides
Authors: Jiang Pingping , Boulet Pascal , Record Marie-Christine
Published: November 2020

Two-dimensional MX (M = Ga, In; X = S, Se, Te) homo- and heterostructures are of interest in electronics and optoelectronics. Structural, electronic and optical properties of bulk and layered MX and GaX/InX heterostructures have been investigated comprehensively using density functional theory (DFT) calculations. Based on the quantum theory of atoms in molecules, topological analyses of bond degree (BD), bond length (BL) and bond angle (BA) have been detailed for interpreting interatomic interactions, hence the structure–property relationship. The X–X BD correlates linearly with the ratio of local potential and kinetic energy, and decreases as X goes from S to Te. For van der Waals (vdW) homo- and heterostructures of GaX and InX, a cubic relationship between microscopic interatomic interaction and macroscopic electromagnetic behavior has been established firstly relating to weighted absolute BD summation and static dielectric constant. A decisive role of vdW interaction in layer-dependent properties has been identified. The GaX/InX heterostructures have bandgaps in the range 0.23–1.49 eV, absorption coefficients over 10−5 cm−1 and maximum conversion efficiency over 27%. Under strain, discordant BD evolutions are responsible for the exclusively distributed electrons and holes in sublayers of GaX/InX. Meanwhile, the interlayer BA adjustment with lattice mismatch explains the constraint-free lattice of the vdW heterostructure.
Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation
Authors: Pani Arianna , Giossi Riccardo , Menichelli Danilo , Fittipaldo Veronica Andrea , Agnelli Francesca , Inglese Elvira , Romandini Alessandra , Roncato Rossana , Pintaudi Basilio , Del Sole Francesco , Scaglione Francesco
Published: November 2020

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.
The Alpha-Lipoic Acid Improves Survival and Prevents Irinotecan-Induced Inflammation and Intestinal Dysmotility in Mice
Authors: Costa Daniely V. S. , Costa Deiziane V. S. , Sousa Caren N. S. , Silva Angeline M. H. P. , Medeiros Ingridy S. , Martins Dainesy S. , Martins Conceição S. , Pequeno Ana L. V. , Lima-Júnior Roberto C. P. , Soares Pedro M. G. , Vasconcelos Silvânia M. M. , Brito Gerly A. C. , Souza Emmanuel P.
Published: November 2020

Irinotecan, an anticancer drug, induces diarrhea and intestinal inflammation, resulting in an increase in the cost of care and in treatment delays. In this study, we investigated whether alpha-lipoic acid (α-LA) could improve irinotecan-mediated intestinal inflammation, diarrhea and dysmotility. Intestinal mucositis was induced by irinotecan injection (75 mg/kg, i.p., for 4 days) in Swiss mice. α-LA (50, 100 or 200 mg/kg, gavage) was administered daily 1 h before the injection of irinotecan. Duodenum tissues were obtained for inflammation and proliferation analysis. The outcomes: diarrhea, intestinal dysmotility, weight body loss and survival were evaluated. Compared with the control condition, irinotecan diminished (p < 0.05) intestinal villus height, caused a loss of crypt integrity and intense inflammatory cell infiltration, increased myeloperoxidase (MPO), IL-6 and IL-1β levels and decreased reduced glutathione (GSH) levels in duodenum segments and increased gastric retention and decreased liquid retention in the medial intestinal segment, resulting in increased intestinal transit, severe diarrhea and reduced survival (approximately 72%). Furthermore, α-LA (200 mg/kg) pretreatment ameliorated (p < 0.05) these irinotecan-induced effects. Our findings show that α-LA reduced irinotecan-induced inflammation, intestinal dysmotility and diarrhea, resulting in improved survival. α-LA may be a useful therapeutic agent for the treatment of gut dysmotility in patients with intestinal mucositis associated with irinotecan treatment.
Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling to Predict the Impact of CYP2C9 Genetic Polymorphisms, Co-Medication and Formulation on the Pharmacokinetics and Pharmacodynamics of Flurbiprofen
Authors: Loisios-Konstantinidis Ioannis , Cristofoletti Rodrigo , Jamei Masoud , Turner David , Dressman Jennifer
Published: November 2020

Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50–300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ≥ 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40–300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.
The Importance of Root Interactions in Field Bean/Triticale Intercrops
Authors: Esnarriaga Dayana N. , Mariotti Marco , Cardelli Roberto , Arduini Iduna
Published: November 2020

To highlight the contribution of belowground interactions to biomass and N and P yields, field bean and triticale were grown in a P-poor soil as sole crops and as replacement intercrops at two N levels. The shoots were always in contact, while the roots of adjacent rows were free to interact or were completely separated. This allowed simultaneous testing the intraspecific and interspecific competition between rows, which to our knowledge has not been studied before. Root biomass, distribution in soil, morphometry, and functional traits were determined, together with the nodule number and biomass. The Land Equivalent Ratio for shoot biomass and N and P yield were higher than 1 when roots were in contact, and markedly lower when they were separated. This demonstrates the positive contribution of root interactions, which in field bean, consisted of increased root elongation without changes in biomass and nutrient status; in triticale, of increased N and P uptake efficiency and reduced biomass partitioning to roots. The soil-plant processes underlying intercrop advantage led to complementarity in N sources with low N inputs and facilitated N and P uptake with high N inputs, which demonstrates that intercropping could be profitable in both low and high input agriculture.
Thermomechanical Modeling of Microstructure Evolution Caused by Strain-Induced Crystallization
Authors: Aygün Serhat , Klinge Sandra
Published: November 2020

The present contribution deals with the thermomechanical modeling of the strain-induced crystallization in unfilled polymers. This phenomenon significantly influences mechanical and thermal properties of polymers and has to be taken into consideration when planning manufacturing processes as well as applications of the final product. In order to simultaneously capture both kinds of effects, the model proposed starts by introducing a triple decomposition of the deformation gradient and furthermore uses thermodynamic framework for material modeling based on the Coleman–Noll procedure and minimum principle of the dissipation potential, which requires suitable assumptions for the Helmholtz free energy and the dissipation potential. The chosen setup yields evolution equations which are able to simulate the formation and the degradation of crystalline regions accompanied by the temperature change during a cyclic tensile test. The boundary value problem corresponding to the described process includes the balance of linear momentum and balance of energy and serves as a basis for the numerical implementation within an FEM code. The paper closes with the numerical examples showing the microstructure evolution and temperature distribution for different material samples.
Effects of Waste Expanded Polypropylene as Recycled Matrix on the Flexural, Impact, and Heat Deflection Temperature Properties of Kenaf Fiber/Polypropylene Composites
Authors: Kim Junghoon , Cho Donghwan
Published: November 2020

Waste Expanded polypropylene (EPP) was utilized as recycled matrix for kenaf fiber-reinforced polypropylene (PP) composites produced using chopped kenaf fibers and crushed EPP waste. The flexural properties, impact strength, and heat deflection temperature (HDT) of kenaf fiber/PP composites were highly enhanced by using waste EPP, compared to those by using virgin PP. The flexural modulus and strength of the composites with waste EPP were 98% and 55% higher than those with virgin PP at the same kenaf contents, respectively. The Izod impact strength and HDT were 31% and 12% higher with waste EPP than with virgin PP, respectively. The present study indicates that waste EPP would be feasible as recycled matrix for replacing conventional PP matrix in natural fiber composites.
Economic Analysis of a Freeze-Drying Cycle
Authors: Stratta Lorenzo , Capozzi Luigi C. , Franzino Simone , Pisano Roberto
Published: November 2020

Freeze-drying has always been considered an extremely expensive procedure to dehydrate food or pharmaceutical products, and for this reason, it has been employed only if strictly necessary or when the high added value of the final product could justify the costs. However, little effort has been made to analyze the factors that make this technology so unaffordable. In this work, a model was proposed to calculate in detail the operational (OC) and capital costs (CC) of a freeze-drying cycle and an evaluation of the process bottlenecks was made. The main result is that the process itself, contrary to the classic belief, is not the most expensive part of freeze-drying, while the initial investment is the real limiting factor. Under this consideration, the optimization of a freeze-drying cycle should be formulated in order to fit more cycles in the lifespan of the apparatus, instead of merely reducing the power consumption of the machine.