bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Synbiotics on the Fecal Microbiome and Metabolomic Profiles of Healthy Research Dogs Administered Antibiotics: A Randomized, Controlled Trial
Authors: Whittemore Jacqueline C. , Price Joshua M. , Moyers Tamberlyn , Suchodolski Jan S.
Published: May 2021

Background: Antibiotic-associated gastrointestinal signs occurred in 100% of dogs administered enrofloxacin with metronidazole in a previous study, and signs partially were mitigated by synbiotics. The objective of this randomized, double-blinded, placebo-controlled trial was to compare the fecal microbiome and metabolome of dogs administered enrofloxacin and metronidazole, followed by either a placebo or a bacterial/yeast synbiotic combination.

Methods: Twenty-two healthy research dogs were randomized to two treatment groups. There were three study periods: baseline, treatment, and washout. Dogs were administered enrofloxacin (10 mg/kg qd) and metronidazole (12.5 mg/kg BID), followed 1 h later by placebo or a commercially-available synbiotic combination (BID), per os for 21 days with reevaluation 56 days thereafter. Fecal samples were collected on days 5–7 (baseline), 26–28, and 82–84. The fecal microbiome was analyzed by qPCR and sequencing of 16S rRNA genes; time-of-flight mass spectrometry was used to determine metabolomic profiles. Split plot repeated measures mixed model ANOVA was used to compare results between treatment groups. P < 0.05 was considered significant, with Benjamini and Hochberg's False Discovery Rate used to adjust for multiple comparisons.

Results: Alpha diversity metrics differed significantly over time in both treatment groups, with incomplete recovery by days 82–84. Beta diversity and the dysbiosis index differed significantly over time and between treatment groups, with incomplete recovery at days 82–84 for dogs in the placebo group. Significant group-by-time interactions were noted for 15 genera, including Adlercreutzia, Bifidobacterium, Slackia, Turicibacter, Clostridium (including C. hiranonis) [Ruminococcus], Erysipelotrichaceae_g_, [Eubacterium], and Succinivibrionaceae_g_. Concurrent group and time effects were present for six genera, including Collinsella, Ruminococcaceae_g_, and Prevotella. Metabolite profiles differed significantly by group-by-time, group, and time for 28, 20, and 192 metabolites, respectively. These included short-chain fatty acid, bile acid, tryptophan, sphingolipid, benzoic acid, and cinnaminic acid metabolites, as well as fucose and ethanolamine. Changes in many taxa and metabolites persisted through days 82–84.

Conclusion: Antibiotic administration causes sustained dysbiosis and dysmetabolism in dogs. Significant group-by-time interactions were noted for a number of taxa and metabolites, potentially contributing to decreased antibiotic-induced gastrointestinal effects in dogs administered synbiotics.
Zoonotic Rickettsia Species in Small Ruminant Ticks From Tunisia
Authors: Belkahia Hanène , Selmi Rachid , Zamiti Sayed , Daaloul-Jedidi Monia , Messadi Lilia , Ben Said Mourad
Published: May 2021

Tick-borne rickettsioses present a significant public health threat among emerging tick-borne diseases. In Tunisia, little is known about tick-borne Rickettsia pathogens. Therefore, the aim of this study was to investigate the presence of Rickettsia species in small ruminant ticks from Tunisia. Adult ticks (n = 694) were collected from goats and sheep in northern Tunisia. Obtained ticks were identified as Rhipicephalus turanicus (n = 434) and Rhipicephalus sanguineus sensu lato (n = 260). Selected ticks (n = 666) were screened for the presence of Rickettsia spp. by PCR targeting a partial sequence of the ompB gene followed by sequence analysis. Rickettsial DNA was detected in 122 (18.3%) tested tick samples. The infection rates in Rh. turanicus and Rh. sanguineus s.l. ticks were 23.4 and 9.5%, respectively. The overall prevalence of rickettsial DNA was markedly higher in ticks collected from goats (23.2%) compared to those infesting sheep (7.9%). The detection of rickettsial DNA was significantly higher in ticks from the governorate of Beja (39.0%) than those from the governorate of Bizerte (13.9%). Two additional genes, the outer membrane protein A gene (ompA) and the citrate synthase gene (gltA), were also targeted for further characterization of the detected Rickettsia species. Genotyping and phylogenetic analysis based on partial sequences (n = 106) of the three different genes revealed that positive ticks are infected with different isolates of two Spotted Fever Group (SFG) Rickettsia, namely, Rickettsia massiliae and Rickettsia monacensis, closely related to those infecting camels and associated ticks from Tunisia, and humans and small ruminant ticks from neighboring countries like Italy, France, and Spain.
A Neural Network Based Dynamic Control Method for Soft Pneumatic Actuator with Symmetrical Chambers
Authors: Li Yiqing , Cao Yan , Jia Feng
Published: May 2021

Dynamic modeling and control of the soft pneumatic actuators are challenging research. In this paper, a neural network based dynamic control method used for a soft pneumatic actuator with symmetrical chambers is proposed. The neural network is introduced to create the dynamic model for predicting the state of the actuator. In this dynamic model, the effect of the uninflated rubber block on bending deformation is considered. Both pressures of the actuator are used for predicting the state of the actuator during the bending motion. The controller is designed based on this dynamic model for trajectory tracking control. Three types of trajectory tracking control experiments are performed to validate the proposed method. The results show that the proposed control method can control the motion of the actuator and track the trajectory effectively.
Numerical and Experimental Investigation of Longitudinal Oscillations in Hall Thrusters
Authors: Giannetti Vittorio , Saravia Manuel Martín , Leporini Luca , Camarri Simone , Andreussi Tommaso
Published: May 2021

One of the main oscillatory modes found ubiquitously in Hall thrusters is the so-called breathing mode. This is recognized as a relatively low-frequency (10–30 kHz), longitudinal oscillation of the discharge current and plasma parameters. In this paper, we present a synergic experimental and numerical investigation of the breathing mode in a 5 kW-class Hall thruster. To this aim, we propose the use of an informed 1D fully-fluid model to provide augmented data with respect to available experimental measurements. The experimental data consists of two datasets, i.e., the discharge current signal and the local near-plume plasma properties measured at high-frequency with a fast-diving triple Langmuir probe. The model is calibrated on the discharge current signal and its accuracy is assessed by comparing predictions against the available measurements of the near-plume plasma properties. It is shown that the model can be calibrated using the discharge current signal, which is easy to measure, and that, once calibrated, it can predict with reasonable accuracy the spatio-temporal distributions of the plasma properties, which would be difficult to measure or estimate otherwise. Finally, we describe how the augmented data obtained through the combination of experiments and calibrated model can provide insight into the breathing mode oscillations and the evolution of plasma properties.
Innovative Mechanical Design Strategy for Actualizing 80 kg-Class X-Band Active SAR Small Satellite of S-STEP
Authors: Kwon Seong-Cheol , Son Ji-Hae , Song Sung-Chan , Park Jin-Han , Koo Kyung-Rae , Oh Hyun-Ung
Published: May 2021

The Small SAR Technology Experimental Project (S-STEP) mission aims to develop a new (space-based 80 kg-class active X-band synthetic aperture radar (SAR)) satellite with a main imaging mode of 1 m resolution stripmap. In the S-STEP mission, to achieve the design goal of developing faster, cheaper, better, and lighter small SAR satellite systems, innovative thermo-mechanical design approaches have been proposed and investigated. The major design approaches are the bus-payload integrated flat plate-type structure, multifunctional transmit/receive (TR) module, and dedicated vibration-free orbit deployer (VFOD) with the function of whole spacecraft vibration isolation. To validate the feasibility of the innovative mechanical design of S-STEP, a structural analysis considering launch and on-orbit environments is performed. In addition, development test results are presented to confirm the effectiveness of the proposed design approach for VFOD.
Novel Structure and Thermal Design and Analysis for CubeSats in Formation Flying
Authors: Park Yeon-Kyu , Kim Geuk-Nam , Park Sang-Young
Published: May 2021

The CANYVAL-C (CubeSat Astronomy by NASA and Yonsei using a virtual telescope alignment for coronagraph) is a space science demonstration mission that involves taking several images of the solar corona with two CubeSats—1U CubeSat (Timon) and 2U CubeSat (Pumbaa)—in formation flying. In this study, we developed and evaluated structural and thermal designs of the CubeSats Timon and Pumbaa through finite element analyses, considering the nonlinearity effects of the nylon wire of the deployable solar panels installed in Pumbaa. On-orbit thermal analyses were performed with an accurate analytical model for a visible camera on Timon and a micro propulsion system on Pumbaa, which has a narrow operating temperature range. Finally, the analytical models were correlated for enhancing the reliability of the numerical analysis. The test results indicated that the CubeSats are structurally safe with respect to the launch environment and can activate each component under the space thermal environment. The natural frequency of the nylon wire for the deployable solar panels was found to increase significantly as the wire was tightened strongly. The conditions of the thermal vacuum and cycling testing were implemented in the thermal analytical model, which reduced the differences between the analysis and testing.
Automated Chicken Counting in Surveillance Camera Environments Based on the Point Supervision Algorithm: LC-DenseFCN
Authors: Cao Liangben , Xiao Zihan , Liao Xianghui , Yao Yuanzhou , Wu Kangjie , Mu Jiong , Li Jun , Pu Haibo
Published: May 2021

The density of a chicken population has a great influence on the health and growth of the chickens. For free-range chicken producers, an appropriate population density can increase their economic benefit and be utilized for estimating the economic value of the flock. However, it is very difficult to calculate the density of chickens quickly and accurately because of the complicated environmental background and the dynamic number of chickens. Therefore, we propose an automated method for quickly and accurately counting the number of chickens on a chicken farm, rather than doing so manually. The contributions of this paper are twofold: (1) we innovatively designed a full convolutional network—DenseFCN—and counted the chickens in an image using the method of point supervision, which achieved an accuracy of 93.84% and 9.27 frames per second (FPS); (2) the point supervision method was used to detect the density of chickens. Compared with the current mainstream object detection method, the higher effectiveness of this method was proven. From the performance evaluation of the algorithm, the proposed method is practical for measuring the density statistics of chickens in a farm environment and provides a new feasible tool for the density estimation of farm poultry breeding.
Characterization of Soil Organic Matter Individual Fractions (Fulvic Acids, Humic Acids, and Humins) by Spectroscopic and Electrochemical Techniques in Agricultural Soils
Authors: Ukalska-Jaruga Aleksandra , Bejger Romualda , Debaene Guillaume , Smreczak Bożena
Published: May 2021

The objective of this paper was to investigate the molecular characterization of soil organic matter fractions (humic substances (HS): fulvic acids-FAs, humic acids-HAs, and humins-HNs), which are the most reactive soil components. A wide spectrum of spectroscopic (UV–VIS and VIS–nearIR), as well as electrochemical (zeta potential, particle size diameter, and polydispersity index), methods were applied to find the relevant differences in the behavior, formation, composition, and sorption properties of HS fractions derived from various soils. Soil material (n = 30) used for the study were sampled from the surface layer (0–30 cm) of agricultural soils. FAs and HAs were isolated by sequential extraction in alkaline and acidic solutions, according to the International Humic Substances Society method, while HNs was determined in the soil residue (after FAs and HAs extraction) by mineral fraction digestion using a 0.1M HCL/0.3M HF mixture and DMSO. Our study showed that significant differences in the molecular structures of FAs, Has, and HNs occurred. Optical analysis confirmed the lower molecular weight of FAs with high amount of lignin-like compounds and the higher weighted aliphatic–aromatic structure of HAs. The HNs were characterized by a very pronounced and strong condensed structure associated with the highest molecular weight. HAs and HNs molecules exhibited an abundance of acidic, phenolic, and amine functional groups at the aromatic ring and aliphatic chains, while FAs mainly showed the presence of methyl, methylene, ethenyl, and carboxyl reactive groups. HS was characterized by high polydispersity related with their structure. FAs were characterized by ellipsoidal shape as being associated to the long aliphatic chains, while HAs and HNs revealed a smaller particle diameter and a more spherical shape caused by the higher intermolecular forcing between the particles. The observed trends directly indicate that individual HS fractions differ in behavior, formation, composition, and sorption properties, which reflects their binding potential to other molecules depending on soil properties resulting from their type. The determined properties of individual HS fractions are presented as averaged characteristics over the examined soils with different physico-chemical properties.
Bioactive Coatings with Ag-Camphorimine Complexes to Prevent Surface Colonization by the Pathogenic Yeast Candida albicans
Authors: Pinheiro M. Joana F. , Costa Joana P. , Marques Fernanda , Mira Nuno P. , Carvalho M. Fernanda N. N. , Alves Marta M.
Published: May 2021

Currently there is a gap between the rate of new antifungal development and the emergence of resistance among Candida clinical strains, particularly threatened by the extreme adhesiveness of C. albicans to indwelling medical devices. Two silver camphorimine complexes, [Ag(OH){OC10H14N(C6H4)2NC10H14O}] (compound P) and [{Ag(OC10H14NC6H4CH3-p)}2(μ-O)] (compound Q), are herein demonstrated as having high inhibiting activity towards the growth of Candida albicans and Candida glabrata clinical strains resistant to azoles, the frontline antifungals used in clinical practice. Compounds P and Q were also explored as bioactive coatings to prevent colonization by C. albicans and colonize the surface of indwelling medical devices, resulting in persistent infections. Functionalization of stainless steel with polycaprolactone (PCL) matrix embedded with compounds P or Q was reported for the first time to inhibit the colonization of C. albicans by 82% and 75%, respectively. The coating of PCL loaded with Q or P did not cause cytotoxic effects in mammalian cells, demonstrating the biocompatibility of the explored approach. The identification and further exploration of new approaches for surface engineering based on new molecules that can sensitize resistant strains, as herein demonstrated for complexes P and Q, is a significant step forward to improve the successful treatment of candidiasis.
Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa
Authors: Gallenga Carla Enrica , Lonardi Maria , Pacetti Sofia , Violanti Sara Silvia , Tassinari Paolo , Di Virgilio Francesco , Tognon Mauro , Perri Paolo
Published: May 2021

Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor’s daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.
Synthesis of Amorphous Conjugated Copolymers Based on Dithienosilole-Benzothiadiazole Dicarboxylic Imide with Tuned Optical Band Gaps and High Thermal Stability
Authors: Murad Ary R. , Dannoun Elham M. A. , Aziz Shujahadeen B. , Iraqi Ahmed , Abdullah Sozan N. , Nofal Muaffaq M. , Abdullah Ranjdar M.
Published: May 2021

Two alternating copolymers of dithienosilole (DTS) were designed and synthesized with small optical band gaps, flanked by thienyl units as electron-donor moieties and benzothiadiazole dicarboxylic imide (BTDI) as electron-acceptor moieties. The BTDI moieties were anchored to two different solubilizing side chains, namely 3,7-dimethyloctyl and n-octyl chains. An analysis of the effect of the electrochemical, optical, thermal, and structural characteristics of the resulting polymers along with their solubility and molecular weight is the subject of this paper. The Stille polymerization was used to synthesize PDTSDTBTDI-DMO and PDTSDTBTDI-8. The average molecular weight of PDTSDTBTDI-DMO and PDTSDTBTDI-8 is 14,600 and 5700 g mol−1, respectively. Both polymers have shown equivalent optical band gaps around 1.4 eV. The highest occupied molecular orbital (HOMO) levels of the polymers were comparable, around −5.2 eV. The lowest unoccupied molecular orbital (LUMO) values were −3.56 and −3.45 eV for PDTSDTBTDI-DMO and PDTSDTBTDI-8, respectively. At decomposition temperatures above 350 °C, both copolymers showed strong thermal stability. The studies of powder X-ray diffraction (XRD) have shown that they are amorphous in a solid-state.
Chimney Sweeping Robot Based on a Pneumatic Actuator
Authors: Sinčák Peter Ján , Virgala Ivan , Kelemen Michal , Prada Erik , Bobovský Zdenko , Kot Tomáš
Published: May 2021

The need of improving the quality of professions led to the idea of simplification of processes during chimney sweeping. These processes have been essentially the same for tens of years. The goal of this paper is to bring an automation element into the chimney sweeping process, making the job easier for the chimney sweeper. In this paper, an essentially in-pipe robot is presented, which uses brushes to move while simultaneously cleaning the chimney or pipeline. The problem of the robot motion was reduced using an in-pipe robot due to the environments and obstacles that the robot has to face. An approach of using a pneumatic actuator for motion is presented along with the mechanical design. The next part of this paper is focused on the mathematical model of the robot motion, as well as its simulation and testing in the experimental pipeline. The simulations were compared with the experimental measurements and a few analyses were conducted describing the simulation model and its differences with the real robot, as well as considering certain parameters and their impact on the performance of the robot. The results are discussed at the end of the paper.
A Machine Learning-Based Seismic Data Compression and Interpretation Using a Novel Shifted-Matrix Decomposition Algorithm
Authors: Brankovic Milan , Gildin Eduardo , Gibson Richard L. , Everett Mark E.
Published: May 2021

Seismic data provides integral information in geophysical exploration, for locating hydrocarbon rich areas as well as for fracture monitoring during well stimulation. Because of its high frequency acquisition rate and dense spatial sampling, distributed acoustic sensing (DAS) has seen increasing application in microseimic monitoring. Given large volumes of data to be analyzed in real-time and impractical memory and storage requirements, fast compression and accurate interpretation methods are necessary for real-time monitoring campaigns using DAS. In response to the developments in data acquisition, we have created shifted-matrix decomposition (SMD) to compress seismic data by storing it into pairs of singular vectors coupled with shift vectors. This is achieved by shifting the columns of a matrix of seismic data before applying singular value decomposition (SVD) to it to extract a pair of singular vectors. The purpose of SMD is data denoising as well as compression, as reconstructing seismic data from its compressed form creates a denoised version of the original data. By analyzing the data in its compressed form, we can also run signal detection and velocity estimation analysis. Therefore, the developed algorithm can simultaneously compress and denoise seismic data while also analyzing compressed data to estimate signal presence and wave velocities. To show its efficiency, we compare SMD to local SVD and structure-oriented SVD, which are similar SVD-based methods used only for denoising seismic data. While the development of SMD is motivated by the increasing use of DAS, SMD can be applied to any seismic data obtained from a large number of receivers. For example, here we present initial applications of SMD to readily available marine seismic data.
A Study of Features and Deep Neural Network Architectures and Hyper-Parameters for Domestic Audio Classification
Authors: Copiaco Abigail , Ritz Christian , Abdulaziz Nidhal , Fasciani Stefano
Published: May 2021

Recent methodologies for audio classification frequently involve cepstral and spectral features, applied to single channel recordings of acoustic scenes and events. Further, the concept of transfer learning has been widely used over the years, and has proven to provide an efficient alternative to training neural networks from scratch. The lower time and resource requirements when using pre-trained models allows for more versatility in developing system classification approaches. However, information on classification performance when using different features for multi-channel recordings is often limited. Furthermore, pre-trained networks are initially trained on bigger databases and are often unnecessarily large. This poses a challenge when developing systems for devices with limited computational resources, such as mobile or embedded devices. This paper presents a detailed study of the most apparent and widely-used cepstral and spectral features for multi-channel audio applications. Accordingly, we propose the use of spectro-temporal features. Additionally, the paper details the development of a compact version of the AlexNet model for computationally-limited platforms through studies of performances against various architectural and parameter modifications of the original network. The aim is to minimize the network size while maintaining the series network architecture and preserving the classification accuracy. Considering that other state-of-the-art compact networks present complex directed acyclic graphs, a series architecture proposes an advantage in customizability. Experimentation was carried out through Matlab, using a database that we have generated for this task, which composes of four-channel synthetic recordings of both sound events and scenes. The top performing methodology resulted in a weighted F1-score of 87.92% for scalogram features classified via the modified AlexNet-33 network, which has a size of 14.33 MB. The AlexNet network returned 86.24% at a size of 222.71 MB.
Developmental Toxicity and Thyroid Endocrine Disruption of Polyhexamethylene Guanidine Hydrochloride and Humidifier Disinfectant in Zebrafish Larvae
Authors: Park Suhyun , Kim Hyojin , Ji Kyunghee
Published: May 2021

Polyhexamethylene guanidine (PHMG), a major component of humidifier disinfectants (HDs), is responsible for the outbreak of pulmonary diseases in pregnant women and children in South Korea. This study aims to characterize the developmental toxicity and thyroid endocrine disruption of Vegetable Home Cleanup HD and its main component, PHMG-hydrochloride (PHMG-H), in zebrafish embryo/larvae after a 7-d exposure. Acute lethality, development, whole-body thyroid hormones, and transcription of genes related to the hypothalamus-pituitary-thyroid axis were investigated. Zebrafish embryos exposed to the actual-use concentration (0.6%) of HD exhibited significant embryo coagulation and larval mortality. The concentration of triiodothyronine (T3) was significantly high in fish exposed to 0.4 mg/L PHMG-H, accompanied by the downregulation of the tshβ gene. These results suggest a feedback mechanism for the regulation of increased T3 levels. Significant decrease of thyroxine (T4) concentration, increase of T3/T4 ratio, and upregulation of the deio2 gene in fish exposed to PHMG-H suggested that there was an increase in the active T3 due to the catalysis of outer ring deiodination. Future research is required to determine the factors that contribute to the differences in toxicity between the two counter ions of PHMG.
Current View on Green Tea Catechins Formulations, Their Interactions with Selected Drugs, and Prospective Applications for Various Health Conditions
Authors: Cerbin-Koczorowska Magdalena , Waszyk-Nowaczyk Magdalena , Bakun Paweł , Goslinski Tomasz , Koczorowski Tomasz
Published: May 2021

Green tea extract (GTE) is one of the most popular beverages globally, traditionally prepared from Camelia sinensis leaves. Therefore, it is beneficial to define the impact of GTE and its ingredients on the human organism. Epigallocatechin-3-O-gallate (EGCG) is the most abundant catechin in green tea leaves, belonging to the group of tannins and flavonoids, demonstrating pharmacological activity, but so far, it has not been applied as a drug. This is because EGCG does not present sufficient stability and quickly decomposes through epimerization or autooxidation mechanisms under the influence of light, temperature, changes in pH, or the presence of oxygen. Another limiting factor is EGCG’s low bioavailability after oral administration. Nevertheless, the growing market of dietary supplements together with increasing growing consumption of green tea extracts should prompt us to pay more attention to the safety of both EGCG itself, as well as its influence on other simultaneously used drugs. Previously published data confirm the relationship between healthcare professionals’ access to professional knowledge and their willingness to engage in patient education. For this reason, in this review article, we report the formulations of EGCG and GTE, discuss the data on the safety of EGCG and its possible interactions with drugs, as well as gather various recommendations from medical specialists. Particular attention should be paid to the consumption of green tea during pregnancy and breastfeeding, as well as in the elderly. Patients taking clozapine, digoxin, and warfarin should avoid consuming GTE extracts and dietary supplements containing EGCG. Professional consultation seems especially important for patients treated with statins, calcium channel blockers, or sildenafil.
Influence of θ′ Phase Cutting on Precipitate Hardening of Al–Cu Alloy during Prolonged Plastic Deformation: Molecular Dynamics and Continuum Modeling
Authors: Krasnikov Vasiliy S. , Mayer Alexander E. , Pogorelko Victor V. , Gazizov Marat R.
Published: May 2021

We investigate the prolonged plastic deformation of aluminum containing θ′ phase with a multistage approach combining molecular dynamics (MD), continuum modeling (CM) and discrete dislocation dynamics (DDD). The time of performed MD calculations is sufficient for about a hundred dislocation–precipitate interactions. With this number of interactions, the inclusion of θ′ is not only cut, but also scattered into individual copper atoms in an aluminum matrix. Damage to the crystal structure of inclusion and activation of the cross-slip of dislocation segments cause a decrease in acting stresses in the MD system. The rate of this effect depends on θ′ diameter and occurs faster for small inclusions. The effect of decreasing the resistance of precipitate is further introduced into the dislocation–precipitate interaction CM by reducing the precipitate effective diameter with an increase in the number of interactions. A model of dislocation–precipitate interaction accounting for the softening of inclusions is further implemented into DDD. Dependences of flow stress in aluminum with θ′ phases on volume fraction and typical diameter of precipitates are obtained. Manifestation of inclusion softening is possible in such an alloy, which leads to the flow stress decrease during deformation. The range of volume fractions and typical diameters of θ′ phases corresponding to the possible decrease in flow stress is distinguished.
Traditional Conservation and Storage Methods for Ancient Chinese Painting and Calligraphy on Silk Manuscripts
Authors: Ren Wei , Cao Na
Published: May 2021

This study investigated traditional conservation and storage methods for Chinese silk manuscripts containing painting and calligraphy from the Warring States period (475–221 BC), the Qin dynasty (221–207 BC), the Han dynasty (202–8 BC; AD 25–220), and from the end of the Han to the present. At present, there is gap in the literature regarding the application of such methods to these works. The study methods include a literature review (classical and contemporary sources), expert interviews, and observation of traditional masters. The findings provide an improved understanding of the development of traditional technologies used for painting and calligraphy conservation since 475 BC. In this way, this work contributes to the body of knowledge regarding traditional conservation and storage methods, including mounting practices, scroll unfolding, and box storage.
Meta-Analysis—Correlation between Spiral Ganglion Cell Counts and Speech Perception with a Cochlear Implant
Authors: Cheng Yew-Song , Svirsky Mario A.
Published: May 2021

The presence of spiral ganglion cells (SGCs) is widely accepted to be a prerequisite for successful speech perception with a cochlear implant (CI), because SGCs provide the only known conduit between the implant electrode and the central auditory system. By extension, it has been hypothesized that the number of SGCs might be an important factor in CI outcomes. An impressive body of work has been published on findings from the laborious process of collecting temporal bones from CI users and counting the number of SGCs to correlate those numbers with speech perception scores, but the findings thus far have been conflicting. We performed a meta-analysis of all published studies with the hope that combining existing data may help us reach a more definitive conclusion about the relationship between SGC count and speech perception scores in adults.
In-House, Fast FDM Prototyping of a Custom Cutting Guide for a Lower-Risk Pediatric Femoral Osteotomy
Authors: Frizziero Leonardo , Santi Gian Maria , Leon-Cardenas Christian , Donnici Giampiero , Liverani Alfredo , Papaleo Paola , Napolitano Francesca , Pagliari Curzio , Di Gennaro Giovanni Luigi , Stallone Stefano , Stilli Stefano , Trisolino Giovanni , Zarantonello Paola
Published: May 2021

Three-dimensional printed custom cutting guides (CCGs) are becoming more and more investigated in medical literature, as a patient-specific approach is often desired and very much needed in today’s surgical practice. Three-dimensional printing applications and computer-aided surgical simulations (CASS) allow for meticulous preoperatory planning and substantial reductions of operating time and risk of human error. However, several limitations seem to slow the large-scale adoption of 3D printed CCGs. CAD designing and 3D printing skills are inevitably needed to develop workflow and address the study; therefore, hospitals are pushed to include third-party collaboration, from highly specialized medical centers to industrial engineering companies, thus increasing the time and cost of labor. The aim of this study was to move towards the feasibility of an in-house, low-cost CCG 3D printing methodology for pediatric orthopedic (PO) surgery. The prototype of a femoral cutting guide was developed for its application at the IOR—Rizzoli Orthopedic Institute of Bologna. The element was printed with an entry-level 3D printer with a high-temperature PLA fiber, whose thermomechanical properties can withstand common steam heat sterilization without bending or losing the original geometry. This methodology allowed for extensive preoperatory planning that would likewise reduce the overall surgery time, whilst reducing the risks related to the intervention.
Risk of Chronic Obstructive Pulmonary Disease Exacerbation in Patients Who Use Methotrexate—A Nationwide Study of 58,580 Outpatients
Authors: Bergsøe Christina Marisa , Sivapalan Pradeesh , Saeed Mohamad Isam , Eklöf Josefin , Saghir Zaigham , Sørensen Rikke , Biering-Sørensen Tor , Jensen Jens-Ulrik Stæhr
Published: May 2021

Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent acute exacerbations and require repeated courses of corticosteroid therapy, which may lead to adverse effects. Methotrexate (MTX) has anti-inflammatory properties. The objective of this study was to describe the risk of COPD exacerbation in patients exposed to MTX. In this nationwide cohort study of 58,580 COPD outpatients, we compared the risk of hospitalization-requiring COPD exacerbation or death within 180 days in MTX vs. non-MTX users in a propensity-score matched study population as well as an unmatched cohort, in which we adjusted for confounders. The use of MTX was associated with a reduction in risk of COPD exacerbation in the propensity-score matched population at 180 days follow-up (HR 0.66, CI 0.66–0.66, p < 0.001). Similar results were shown in our sensitivity analyses at 180-day follow-up on unmatched population and 365-day follow-up on matched and unmatched population (HR 0.76 CI 0.59–0.99, HR 0.81 CI 0.81–0.82 and HR 0.92 CI 0.76–1.11, respectively). MTX was associated with a lower risk of COPD exacerbation within the first six months after study entry. The finding seems biologically plausible and could potentially be a part of the management of COPD patients with many exacerbations.
Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications
Authors: Indini Alice , Grossi Francesco , Mandalà Mario , Taverna Daniela , Audrito Valentina
Published: May 2021

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.
Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice
Authors: Ciarlo Laura , Marzoli Francesca , Minosi Paola , Matarrese Paola , Pieretti Stefano
Published: May 2021

Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes mellitus, leading to painful condition as neuropathic pain. The pathogenetic mechanism of diabetic peripheral neuropathy is very complex, and its understanding could lead to a more suitable therapeutic strategy. In this work, we analyzed the effects of ammonium glycyrrhizinate, a derivate salt of glycyrrhizic acid, on an in vitro system, neuroblastoma cells line SH-SY5Y, and we observed that ammonium glycyrrhizinate was able to prevent cytotoxic effect and mitochondrial fragmentation after high-glucose administration. In an in vivo experiment, we found that a short-repeated treatment with ammonium glycyrrhizinate was able to attenuate neuropathic hyperalgesia in streptozotocin-induced diabetic mice. In conclusion, our results showed that ammonium glycyrrhizinate could ameliorate diabetic peripheral neuropathy, counteracting both in vitro and in vivo effects induced by high glucose, and might represent a complementary medicine for the clinical management of diabetic peripheral neuropathy.
Management of Acute Radiodermatitis in Non-Melanoma Skin Cancer Patients Using Electrospun Nanofibrous Patches Loaded with Pinus halepensis Bark Extract
Authors: Kyritsi Aikaterini , Kikionis Stefanos , Tagka Anna , Koliarakis Nikolaos , Evangelatou Antonia , Papagiannis Panagiotis , Stratigos Alexandros , Karalis Vangelis , Dallas Paraskevas , Vitsos Andreas , Ioannou Efstathia , Roussis Vassilios , Rallis Michail
Published: May 2021

Acute radiodermatitis is the most common side effect in non-melanoma skin cancer patients undergoing radiotherapy. Nonetheless, despite the ongoing progress of clinical trials, no effective regimen has been found yet. In this study, a non-woven patch, comprised of electrospun polymeric micro/nanofibers loaded with an aqueous extract of Pinus halepensis bark (PHBE), was fabricated and clinically tested for its efficacy to prevent radiodermatitis. The bioactivity of the PHBE patch was evaluated in comparison with a medical cream indicated for acute radiodermatitis. Twelve volunteer patients were selected and randomly assigned to two groups, applying either the PHBE patch or the reference cream daily. Evaluation of radiation-induced skin reactions was performed during the radiotherapy period and 1 month afterwards according to the Radiation Therapy Oncology Group (RTOG) grading scale, photo-documentation, patient-reported outcomes (Visual Analog Scale, questionnaire), biophysical measurements (hydration, transepidermal water loss, erythema, melanin), and image analysis. In contrast with the reference product, the PHBE patch showed significant anti-inflammatory activity and restored most skin parameters to normal levels 1 month after completion of radiation therapy. No adverse event was reported, indicating that the application of the PHBE patch can be considered as a safe medical device for prophylactic radiodermatitis treatment.
Childhood Cancer: Occurrence, Treatment and Risk of Second Primary Malignancies
Authors: Zahnreich Sebastian , Schmidberger Heinz
Published: May 2021

Cancer represents the leading cause of disease-related death and treatment-associated morbidity in children with an increasing trend in recent decades worldwide. Nevertheless, the 5-year survival of childhood cancer patients has been raised impressively to more than 80% during the past decades, primarily attributed to improved diagnostic technologies and multiagent cytotoxic regimens. This strong benefit of more efficient tumor control and prolonged survival is compromised by an increased risk of adverse and fatal late sequelae. Long-term survivors of pediatric tumors are at the utmost risk for non-carcinogenic late effects such as cardiomyopathies, neurotoxicity, or pneumopathies, as well as the development of secondary primary malignancies as the most detrimental consequence of genotoxic chemo- and radiotherapy. Promising approaches to reducing the risk of adverse late effects in childhood cancer survivors include high precision irradiation techniques like proton radiotherapy or non-genotoxic targeted therapies and immune-based treatments. However, to date, these therapies are rarely used to treat pediatric cancer patients and survival rates, as well as incidences of late effects, have changed little over the past two decades in this population. Here we provide an overview of the epidemiology and etiology of childhood cancers, current developments for their treatment, and therapy-related adverse late health consequences with a special focus on second primary malignancies.
The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Sakamoto Azusa , Marusawa Hiroyuki , Kojima Yuji , Hasebe Chitomi , Arai Hirotaka , Joko Kouji , Kondo Masahiko , Tsuji Keiji , Sohda Tetsuro , Kimura Hiroyuki , Ogawa Chikara , Uchida Yasushi , Wada Shuichi , Kobashi Haruhiko , Furuta Koichiro , Shigeno Masaya , Kusakabe Atsunori , Akahane Takehiro , Narita Ryoichi , Yoshida Hideo , Mitsuda Akeri , Ide Yasushi , Matsushita Tomomichi , Izumi Namiki ,   on behalf of Japanese Red Cross Liver Study Group
Published: May 2021

Background: Lenvatinib (LEN) has been approved for patients with unresectable hepatocellular carcinoma (u-HCC) since March 2018 in Japan. We performed a retrospective nationwide multicenter study to clarify the clinical characteristics of LEN in real-world practice. Methods: A total of 343 u-HCC patients who received LEN from March 2018 to May 2020 at 23 sites in Japan were registered. Results: During the median observation period of 10.5 months, 143 patients died. In Child-Pugh A (n = 276) and Child-Pugh B (n = 67) patients, the median overall survival (OS) was 21.0 and 9.0 months. The median progression-free survival (PFS) was 8.8 months in Child-Pugh A patients. The objective response rate (ORR) and disease control rate (DCR) according to modified response evaluation criteria in solid tumors (RECIST criteria) were 42.1% and 82.1%. The independent pretreatment factors associated with mortality in all patients were AFP ≥ 400 ng/mL (hazard ratio (HR) 2.00, 95% confidential interval (95% CI) 1.08–2.09, p < 0.0001), modified albumin-bilirubin (ALBI) grade 2b or 3 (HR 1.56, 95% CI 1.09–2.17, p = 0.012), major vascular invasion (HR 1.91, 95% CI 1.26–2.89, p = 0.0022), PS > 0 (HR 1.50, 95% CI 1.09–2.08, p = 0.014), and MTT (molecular targeted therapy) experience (HR 2.22, 95% CI 1.56–3.13, p = 0.00038). In the MTT naïve patients with ALBI grade 1 or modified ALBI 2a and BCLC stage B (n = 68), median OS and PFS were 25.3 and 12.3 months. Liver-related adverse events during LEN were the only significant adverse event associated with OS (HR 2.74, 95% CI 1.93–3.88, p < 0.0001). Among the Child-Pugh A patients with extrahepatic metastasis and no major vascular invasion, median PFS in the patients with bone metastasis was significantly shorter than those with lung or adrenal grand metastasis (6.3 vs. 12.5 months, p = 0.0025). Conclusion: LEN showed a high response rate in real-world practice. Pretreatment factors, including ALBI score, AFP, and major vascular invasion are important in making a treatment strategy for patients with u-HCC. The patients with bone metastasis would be candidates for new therapeutic approaches.
Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?
Authors: Klein Klara , Stoiber Dagmar , Sexl Veronika , Witalisz-Siepracka Agnieszka
Published: May 2021

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.
AID Contributes to Accelerated Disease Progression in the TCL1 Mouse Transplant Model for CLL
Authors: Schubert Maria , Gassner Franz Josef , Huemer Michael , Höpner Jan Philip , Akimova Ekaterina , Steiner Markus , Egle Alexander , Greil Richard , Zaborsky Nadja , Geisberger Roland
Published: May 2021

Adaptive somatic mutations conferring treatment resistance and accelerated disease progression is still a major problem in cancer therapy. Additionally in CLL, patients receiving novel, efficient drugs frequently become treatment refractory and eventually relapse. Activation-induced deaminase (AID) is a cytosine deaminase that catalyzes somatic hypermutation of genomic DNA at the immunoglobulin locus in activated B cells. As considerable off-target mutations by AID have been discerned in chronic lymphocytic leukemia, it is essential to investigate to which extent these mutations contribute to disease progression to estimate whether AID inhibition could counteract drug resistance mechanisms. In this study, we examined the TCL1 mouse model for CLL on an AID pro- and deficient background by comparing disease development and mutational landscapes. We provide evidence that AID contributes to the acquisition of somatic cancer-specific mutations also in the TCL1 model and accelerates CLL development particularly in the transplant setting. We conclude that AID is directly determining the fitness of the CLL clone, which prompts further studies to assess the effect of AID inhibition on the occurrence of drug resistance.