bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermographic Stall Detection by Model-Inspired Evaluation of the Dynamic Temperature Behaviour
Authors: Oehme Felix , Suhr Janick , Balaresque Nicholas , Gleichauf Daniel , Sorg Michael , Fischer Andreas
Published: September 2021

Model-inspired signal processing approaches with an enhanced detectability of flow separation on thermographic images are presented. Flow separation causes performance loss, structural loads and increasing acoustic emissions on wind turbine rotor blades. However, due to the low thermal contrast between turbulent and separated flow regions, the non-invasive thermographic visualisation of flow separation is currently only possible for wind tunnel measurements, which are characterised by a high thermal contrast and a small measuring distance. The state-of-the-art signal processing approaches evaluate the surface temperature fluctuation of thermographic image series. However, understanding of the signal measurement chain with a distinct consideration of the influences on the dynamic surface temperature is incomplete. Therefore, designing model-inspired signal processing approaches which provide a high interpretability and a maximum contrast is an open task. The proposed signal processing approaches evaluate the surface response selectively, by using the amplitude information of the surface temperature response to an oscillating input signal or gradient-based for a transient input signal. The approaches are applied to wind tunnel measurements on a rotor blade profile at a near thermodynamic steady state and a transient thermodynamic behaviour at Reynolds numbers that are representative for operational wind turbines. The gradient-based evaluation shows an improved contrast for the detection of flow separation, but is only applicable to profiles with transient thermodynamic behaviour. The amplitude evaluation provides a high degree of interpretability of the processed images based on flow-dependent features and enables for an unambiguous identification of flow separation by a global amplitude minimum close to the separation point. Additionally, an increased spatial resolution for surface modifications is shown, while the contrast between flow regions is significantly decreased. Hence, the proposed approaches allow for an improved identifiability of flow separation with regard to future applications on wind turbines in operation.
Synthesis and Properties of Electrically Conductive/Nitrogen Grain Boundaries Incorporated Ultrananocrystalline Diamond (N-UNCD) Thin Films Grown by Microwave Plasma Chemical Vapor Deposition (MPCVD)
Authors: Salgado-Meza Michelle , Martínez-Rodríguez Guillermo , Tirado-Cantú Pablo , Montijo-Valenzuela Eliel Eduardo , García-Gutiérrez Rafael
Published: September 2021

Research and development have been performed to investigate the effect of total pressure and microwave power on the electrical conductivity of nitrogen (N) atoms’ grain boundaries incorporated ultrananocrystalline diamond (N-UNCD) films grown by microwave plasma chemical vapor deposition (MPCVD). Insertion of N atoms into the UNCD film’s grain boundaries induces N atoms chemical reaction with C-atoms dangling bonds, resulting in release of electrons, which induce electrical conductivity. Four-point probe electrical measurements show that the highest electrically conductive N-UNCD films, produced until now, exhibit electrical resistivity of ~1 Ohm.cm, which is orders of magnitude lower than the ≥106 Ohm.cm for undoped ultrananocrystalline diamond (UNCD) films. X-ray diffraction analysis and Raman spectroscopy revealed that the growth of the N-UNCD films by MPCVD do not produce graphite phase but only crystalline nanodiamond grains. X-ray photoelectron spectroscopy (XPS) analysis confirmed the presence of nitrogen (N) in the N-UNCD films and the high conductivity (no electrical charging is observed during XPS analysis) shown in electrical measurements.
Airflow Dynamics and Aluminum Coating Oxidation Behavior under Electric-Arc Spraying with Airflow Pulsations
Authors: Zakharova Irina , Royanov Vyacheslav , Chigarev Valeriy
Published: September 2021

The paper aims to investigate the airflow dynamics of electric-arc spraying (EAS) with airflow pulsation. The study is focused on the dynamic structure of the airflow with an obstacle in the form of crossed electrodes at the steady and the pulsating air supply (with a frequency up to 120 Hz). The work was fulfilled using a computer simulation, the airflow “shadow” photo visualization, and the microstructure characterization of the coatings formed. It was found that when air flows along the crossed electrodes with a gap of 2 mm, a depression zone appears in the flow with a pressure drop from 0.56 MPa to 0.01 MPa. The air pulsation resulted in a change in a flow’s dynamic structure towards an increase in the length of the depression zone, which covers most of the arc, affecting the liquid metal oxidation. It is established that the frequency of a droplet formation should match the frequency of the airflow pulsation to minimize the metal oxidation. With the air pulsating at about 65 Hz, the oxide volume fraction in the aluminum coating was reduced by 3.6 times compared to the steady airflow. EAS with airflow pulsation has the potential for technological cost reduction.
FlowHaptics: Mid-Air Haptic Representation of Liquid Flow
Authors: Ratsamee Photchara , Orita Yusuke , Kuroda Yoshihiro , Takemura Haruo
Published: September 2021

Water is an essential substance for humans in their daily lives. There are many opportunities for us to come in contact with water, such as cooking, bathing, and swimming. However, few studies have reproduced the sensation of water touching the skin. This study aims to propose a novel midair haptic device, named FlowHaptics, that reproduces the feeling of the force of flowing water over human fingers using multiple air jets. We first estimated the temporal pressure distribution change of water in two-dimensional space using machine-learning-accelerated fluid simulation. We controlled the airflow based on the pressure distribution change obtained from the fluid simulation to reproduce the feeling of flowing water over the fingers using our proposed device, which can control multiple air jets in real time. We performed a psycho-physical evaluation of different flow velocities and a subjective evaluation of different velocity profiles. We found that FlowHaptics reliably created the illusion of the pressure distribution of flowing water on the fingers where the flow velocity could be distinguished within the range of 8.42% to 13.05%, and our estimated flow velocity profile with the configuration of three air jets felt more similar to flowing water when compared to a constant velocity profile according to the users.
Exploring Nanomechanical Properties of Soot Particle Layers by Atomic Force Microscopy Nanoindentation
Authors: De Falco Gianluigi , Carbone Fiorenzo , Commodo Mario , Minutolo Patrizia , D’Anna Andrea
Published: September 2021

In this work, an experimental investigation of the nanomechanical properties of flame-formed carbonaceous particle layers has been performed for the first time by means of Atomic Force Microscopy (AFM). To this aim, carbon nanoparticles with different properties and nanostructures were produced in ethylene/air laminar premixed flames at different residence times. Particles were collected on mica substrates by means of a thermophoretic sampling system and then analyzed by AFM. An experimental procedure based on the combination between semi-contact AFM topography imaging, contact AFM topography imaging and AFM force spectroscopy has been implemented. More specifically, a preliminary topological characterization of the samples was first performed operating AFM in semi-contact mode and then tip-sample interaction forces were measured in contact spectroscopy mode. Finally, semi-contact mode was used to image the indented surface of the samples and to retrieve the projected area of indents. The hardness of investigated samples was obtained from the force–distance curves measured in spectroscopy mode and the images of intends acquired in semi-contact mode. Moreover, the Young’s modulus was measured by fitting the linear part of the retraction force curves using a model based on the Hertz theory. The extreme force sensitivity of this technique (down to nNewton) in addition to the small size of the probe makes it extremely suitable for performing investigation of mechanical properties of materials at the nanoscale. The experimental procedure was successfully tested on reference materials characterized by different plastic behavior, e.g., polyethylene naphthalate and highly oriented pyrolytic graphite. Both hardness and Young’s modulus values obtained from AFM measurements for different soot particle films were discussed.
Design, Modeling, and Analysis of Piezoelectric-Actuated Device for Blood Sampling
Authors: Haldkar Rakesh Kumar , Gupta Vijay Kumar , Sheorey Tanuja , Parinov Ivan A.
Published: September 2021

In recent years, micro electro-mechanical system (MEMS)-based biomedical devices have been investigated by various researchers for biomedicine, disease diagnosis, and liquid drug delivery. The micropump based devices are of considerable significance for accurate drug delivery and disease diagnosis. In the present study, design aspects of the piezoelectric actuated micropump used for extraction of blood sample are presented. A pentagonal microneedle, which is an integral part of the micropump, was used to extract the blood volume. The blood was then delivered to the biosensor, located in the pump chamber, for diagnosis. The purpose of such low-powered devices is to get sufficient blood volume for the diagnostic purpose at the biosensor located within the pump chamber, with a minimum time of actuation, which will eventually cause less pain. ANSYS® simulations were performed on four quarter piezoelectric bimorph actuator (FQPB) at 2.5 volts. The modal and harmonic analysis were carried out with various load conditions for FQPB. The extended microneedle lengths inside the pump chamber showed improved flow characteristics. Enhanced volume flow rate of 1.256 µL/s was obtained at 22,000 Hz applied frequency at the biosensor location.
Exact Scan Patterns of Rotational Risley Prisms Obtained with a Graphical Method: Multi-Parameter Analysis and Design
Authors: Duma Virgil-Florin , Dimb Alexandru-Lucian
Published: September 2021

Rotational Risley prisms are one of the fastest two-dimensional (2D) optomechanical scanning systems. Their drawback is the strong non-linearity of the scan patterns they produce, in contrast to the most common (but slower) raster scanning modalities of 2D dual axis galvanometer scanners (GSs) or Micro-Electro-Mechanical Systems (MEMS) with oscillatory mirrors. The aim of this work is to develop a graphical method, which, to our knowledge, we have introduced to determine and characterize, using a commercially-available mechanical design program (for example CATIA V5R20 (Dassault Systems, Paris, France)) to simulate the exact scan patterns of rotational Risley prisms. Both the maximum and minimum angular and linear deviations of this type of scanner are deduced theoretically to characterize the outer diameter/Field-of-View (FOV) and the inner diameter (of the blind zone) of its ring-shaped patterns, respectively. This multi-parameter analysis is performed in correlation with the shape of the scan patterns, considering the four possible configurations of laser scanners with a pair of rotational Risley prisms, as well as all their parameters: prisms angles, refractive indexes, rotational speeds, distance between the two prisms, and the distance from the system to the scanned plane. Marshall’s synthetic parameters are also considered, i.e., the ratios of the rotational velocities and of the angles of the prisms. Rules-of-thumb for designing this optomechanical scanner are extracted from this analysis, regarding both shapes and dimensions of the scan patterns to be produced. An example of experimental validation completes the mathematical analysis and the performed simulations.
Experimental and Process Modelling Investigation of the Hydrogen Generation from Formic Acid Decomposition Using a Pd/Zn Catalyst
Authors: Hafeez Sanaa , Barlocco Ilaria , Al-Salem Sultan M. , Villa Alberto , Chen Xiaowei , Delgado Juan J. , Manos George , Dimitratos Nikolaos , Constantinou Achilleas
Published: September 2021

The use of hydrogen as a renewable fuel has attracted great attention in recent years. The decomposition of formic acid under mild conditions was investigated using a 2%Pd6Zn4 catalyst in a batch reactor. The results showed that the conversion of formic acid increases with reaction temperature and with the formic acid concentration. A process-simulation model was developed to predict the decomposition of formic acid using 2%Pd6Zn4 in a batch reactor. The model demonstrated very good validation with the experimental work. Further comparisons between the 2%Pd6Zn4 catalyst and a commercial Pd/C catalyst were carried out. It was found that the 2%Pd6Zn4 demonstrated significantly higher conversions when compared with the commercial catalyst.
FTIR Spectroscopy for Identification and Intra-Species Characterization of Serpula lacrymans
Authors: Barboux Rony , Bousta Faisl , Di Martino Patrick
Published: September 2021

The dry rot fungus Serpula lacrymans is the most destructive fungal agent of wood building materials in Europe, Russia, North America, and Japan. The identification of this wood-deteriorating agent and the discrimination of different fungal isolates is very important for the control of buildings in general and for the preservation of cultural heritage in particular. The objective of the study was to develop a Fourier transform infrared (FTIR) method coupled with a partial least square discriminant analysis (PLS-DA) for the sample preparation and identification of S. lacrymans. Five distinct S. lacrymans strains were analysed and compared to two strains of unrelated fungal species. Different methods of mycelial growth, sample preparation, and FTIR spectral data normalisation were compared. FTIR analysis of a harvested mycelium grown on the surface of a polyether sulfone microfiltration membrane deposited on a malt extract agar medium, followed by vector normalization and PLS-DA statistical analysis, resulted in 100% correct attribution at phylum, species, and strain level, regardless of the type of standardization used. This study confirms the applicability of FTIR spectroscopy for the identification of S. lacrymans and the discrimination of different strains belonging to this species.
Assessment of BIM Competencies and Correlation Analysis between Competencies and Career Characteristics of FAB Construction Project Participants
Authors: Lee Songyi , Chung Suwan , Kwon Soonwook , Cho Chung-Suk , Lee Kyuhyup
Published: September 2021

Currently, BIM implementation in domestic FAB construction projects is in such an early stage that they are benchmarking the BIM implementation method applied in the conventional building sector. As such, in order to enhance the usability of BIM in FAB construction projects, it is necessary to have a correct understanding of FAB construction and to apply BIM in accordance with the characteristics of FAB. This requires defining critical BIM competencies needed by the participants of FAB construction projects in undertaking their tasks as well as identifying their current level of competency possessed. Accordingly, this study defined and presented BIM competencies that reflect the characteristics of FAB through the analysis of typical tasks related to FAB construction projects. For this, project participants from three FAB construction project sites in Korea (where BIM was implemented) were recruited, and a survey was conducted on their status of competency level. Moreover, a comparative analysis was conducted focusing on the correlations between their career characteristics (‘Construction project experience’, ‘BIM-based construction project experience’, ‘FAB construction project experience’, ‘BIM-based FAB construction project experience’ and ‘Overall project experiences’) and their current level of BIM competencies. As a result, high correlations were found between BIM competencies and BIM-based FAB construction project experience for the owner group, whereas competency items related to BIM-based construction project experience showed high correlations for the designer group.
The Carbon Emission Reduction Effect of Technological Innovation on the Transportation Industry and Its Spatial Heterogeneity: Evidence from China
Authors: Shi Tao , Si Shucun , Chan Jian , Zhou Lingling
Published: September 2021

The carbon reduction effect of technological innovation in the transportation industry is conducive to China’s anticipated realization of carbon neutrality. Therefore, we evaluated carbon emission reduction effect of technological innovation in the transportation industry in China. Based on the panel data of 30 sample provinces in China (excluding Hong Kong, Macao, Taiwan and Tibet) from 2012 to 2018, using the Moran’I index and Getis-Ord Gi index, this paper analyzes the evolutionary trend and spatial autocorrelation of carbon emission in the transportation industry, and analyzes the impact of technological innovation on carbon emission levels of the transportation industry and its spatiotemporal differences by using the geographical and temporal weighted regression (GTWR) model by using ArcGIS 10.4 software. The conclusions are as follows: The carbon emission level of China’s transportation industry generally has been rising steadily, showing a spatial distribution pattern of high emissions in the east and low emissions in the west. The cold spots are concentrated in the western region, and the hot spots are situated in the central and eastern regions. Technological innovation has a carbon reduction effect on the transportation industry in the eastern and north-eastern regions, while the effect in other regions is not obvious. However, there is an obvious “inverted U-shaped” relationship between technological innovation and the transportation industry’s carbon emissions. The technological innovation in the transportation industry will have a significant carbon reduction effect after breaking through the technical pain points. This carbon reduction effect has a higher effect on the western region than on the eastern region. In addition, the economic development level, the fiscal expenditure proportion of the transportation industry, the higher education level, and the proportion of fixed asset investment in the transportation industry have played a positive role in reducing carbon in the transportation industry, but the spatial heterogeneity of this carbon reduction effect is relatively strong. Therefore, during the “14th Five-Year Plan” development period in China, it is necessary to continuously promote the low-carbon development of the transportation industry with technological innovation, while highlighting the differentiated carbon reduction governance, and consolidating the role of talents and fiscal support.
Microbial Environmental Pollution in ICUs: Results, Trends, and Suggestions from a Long-Lasting Surveillance
Authors: D’Alessandro Daniela , Fabiani Massimo , Appolloni Letizia
Published: September 2021

Intensive care units (ICUs) are special areas in hospitals for patients with severe and life-threatening diseases. ICUs are of several categories, such as neonatal ICUs, cardiac ICUs, neurological ICUs, surgical ICUs, etc. The ICUs’ patients may show a high susceptibility for hospital-acquired infections (HAIs) depending on underlying disease, duration of stay and treatment. ICUs are considered potential reservoirs for (opportunistic) pathogenic microbial strains and the risk of acquiring infection in these hospital environments is higher than in others. Several studies show the role of inanimate surface and equipment contamination in the transmission of pathogens to ICU patients. The aim of this study is to describe the results of 124 sampling campaigns performed during 12 years of microbiological surveillance of five ICUs of different categories, for an overall number of 714 samples (232 from air and 482 from surface), to analyze their trends and to elaborate suggestions to improve ICUs’ environmental quality and patients’ safety.
Periodic Third-Order Problems with a Parameter
Authors: Minhós Feliz , Oliveira Nuno
Published: September 2021

This work concerns with the solvability of third-order periodic fully problems with a weighted parameter, where the nonlinearity must verify only a local monotone condition and no periodic, coercivity or super or sublinearity restrictions are assumed, as usual in the literature. The arguments are based on a new type of lower and upper solutions method, not necessarily well ordered. A Nagumo growth condition and Leray–Schauder’s topological degree theory are the existence tools. Only the existence of solution is studied here and it will remain open the discussion on the non-existence and the multiplicity of solutions. Last section contains a nonlinear third-order differential model for periodic catatonic phenomena, depending on biological and/or chemical parameters.
A Loss of Nuclear—Cytoskeletal Interactions in Vascular Smooth Muscle Cell Differentiation Induced by a Micro-Grooved Collagen Substrate Enabling the Modeling of an In Vivo Cell Arrangement
Authors: Nagayama Kazuaki
Published: September 2021

Vascular smooth muscle cells (VSMCs) remodel vascular walls actively owing to mechanical cues and dedifferentiate to the synthetic phenotype from contractile phenotype in pathological conditions. It is crucial to clarify the mechanisms behind the VSMC phenotypic transition for elucidating their role in the vascular adaptation and repair and for designing engineered tissues. We recently developed novel micro-grooved collagen substrates with “wavy wrinkle” grooves to induce cell–substrate adhesion, morphological polarization, and a tissue-like cell arrangement with cytoskeletal rearrangements similar to those in vascular tissue in vivo. We found that cultivation with this micro-grooved collagen significantly induced VSMC contractile differentiation. Nonetheless, the detailed mechanism underlying the promotion of such VSMC differentiation by micro-grooved collagen has not been clarified yet. Here, we investigated the detailed mechanism of the cell arrangement into a tissue and contractile-differentiation improvement by our micro-grooved collagen substrates in terms of nuclear–cytoskeletal interactions that possibly affect the nuclear mechanotransduction involved in the activation of transcription factors. We found that VSMCs on micro-grooved collagen manifested significant cell arrangement into a tissue and nucleus slimming with a volume reduction in response to the remodeling of the actin cytoskeleton, with consequent inhibition of nuclear shuttling of a transcriptional coactivator, Yes-associated protein (YAP), and improved contractile differentiation. Furthermore, VSMC nuclei rarely deformed during macroscopic cell stretching and featured a loss of nesprin-1–mediated nuclear–cytoskeletal interactions. These results indicate that our micro-grooved collagen induces a cell alignment mimicking in vivo VSMC tissue and promotes contractile differentiation. In such processes of contractile differentiation, mechanical interaction between the nucleus and actin cytoskeleton may diminish to prevent a nuclear disturbance from the excess mechanical stress that might be essential for maintaining vascular functions.
Development of a Quantitative PCR Assay for Four Salmon Species Inhabiting the Yangyangnamdae River Using Environmental DNA
Authors: Fu'adil Amin Muhammad Hilman , Lee Ji-Hyun , Kim Ah Ran , Kim Ju-Kyoung , Lee Chung-Il , Kim Hyun-Woo
Published: September 2021

A species-specific quantitative PCR (qPCR) assay using environmental DNA (eDNA) is a promising tool for both qualitative and quantitative analyses of target species directly from water samples. Despite its reliability, an eDNA-based qPCR assay pipeline has not yet developed to monitor salmon species inhabiting Korean waters, which have been rapidly decreasing. We designed species-specific primers for four Oncorhynchus species inhabiting the eastern coastal waters along the Korean Peninsula. These include primers for two native species (Oncorhynchus keta and O. masou) and two that were introduced (O. mykiss and O. kisutch). The limit of detection and limit of quantification for the four qPCR assays ranged from 4.11 to 10.38 copies and from 30 to 81 copies, respectively, indicating a high sensitivity and specificity across all four species. Following optimization, the qPCR assays were used for the quantitative analyses of the four Oncorhynchus species in the Yangyangnamdae River during the spawning and non-spawning seasons in the year 2019–2020, one of the main rivers where salmon migrate during the spawning season in Korea. The raw copy numbers in all of the examined samples were normalized by PCR inhibition rates to standardize and compare with other studies. Among the four Oncorhynchus species examined, the eDNA concentration of O. keta increased significantly (63.60-fold, p < 0.0001) during the spawning season (November) compared with that in the non-spawning season (March), suggesting that O. keta is the main salmon species migrating through the Yangyangnamdae River. In contrast, we did not detect any differences in eDNA concentration for the other three Oncorhynchus species between the spawning and non-spawning seasons, indicating that their presence does not alter during the year. Their eDNA concentration is also relatively low compared to O. keta, which suggests that small numbers of these three species are present in the river. Overall, these newly developed qPCR assays represent useful monitoring tools for the management of four salmon species in Korean waters.
Ultrasonic Heating Detects Lipiodol Deposition within Liver Tumors after Transarterial Embolization: An In Vivo Approach
Authors: Saito Natsuhiko , Tanaka Toshihiro , Minamiguchi Kiyoyuki , Taiji Ryosuke , Nishiofuku Hideyuki , Matsumoto Takeshi , Hirai Toshiko , Kichikawa Kimihiko , Kawahara Naoki , Matsuda Daiki , Akiyama Iwaki
Published: September 2021

Computed tomography (CT) is the standard method to evaluate Lipiodol deposition after transarterial embolization (TAE) for a long period. However, iodine but not Lipiodol can be observed on CT. A minimally invasive other method to detect Lipiodol has been needed to evaluate accurate evaluation after procedure. The purpose of this study was to evaluate the efficacy of using the rate of change in sound velocity caused by ultrasonic heating to reflect Lipiodol accumulation after TAE in a rat liver tumor model. We analyzed the association of this developed technique with CT images and histological findings. Eight rats bearing N1S1 cells were prepared. After confirmation of tumor development in a rat liver, Lipiodol was injected via the hepatic artery. Seven days after TAE, CT scan and sound velocity changes caused by ultrasonic heating were measured, and then the rats were sacrificed. An ultrasonic pulse-echo method was used to measure the sound velocity. The temperature coefficient of the sound velocity in each treated tumor was evaluated and compared with the mean CT value and the histological Lipiodol accumulation ratio. Pearson’s correlation coefficients were calculated to assess the correlation between the measured values. The correlation coefficient (r) of the mean CT value and histological Lipiodol accumulation ratio was 0.835 (p = 0.010), which was considered statistically significant. Also, those of the temperature coefficient of the sound velocity and the histological Lipiodol accumulation ratio were statistically significant (r = 0.804; p = 0.016). To our knowledge, this is the first study that reported the efficacy of ultrasonic heating to detect Lipiodol accumulation in rat liver tumors after TAE. Our results suggest that the rate of change in sound velocity caused by ultrasonic heating can be used to evaluate Lipiodol accumulation in liver tumors after TAE, and thus could represent an alternative to CT in this application. This new innovative technique is easy to treat and less invasive in terms of avoiding radiation compared with CT.
Measuring Treatment Response in Progressive Multiple Sclerosis—Considerations for Adapting to an Era of Multiple Treatment Options
Authors: Krajnc Nik , Berger Thomas , Bsteh Gabriel
Published: September 2021

Disability in multiple sclerosis accrues predominantly in the progressive forms of the disease. While disease-modifying treatment of relapsing MS has drastically evolved over the last quarter-century, the development of efficient drugs for preventing or at least delaying disability in progressive MS has proven more challenging. In that way, many drugs (especially disease-modifying treatments) have been researched in the aspect of delaying disability progression in patients with a progressive course of the disease. While there are some disease-modifying treatments approved for progressive multiple sclerosis, their effect is moderate and limited mostly to patients with clinical and/or radiological signs of disease activity. Several phase III trials have used different primary outcomes with different time frames to define disease progression and to evaluate the efficacy of a disease-modifying treatment. The lack of sufficiently sensitive outcome measures could be a possible explanation for the negative clinical trials in progressive multiple sclerosis. On the other hand, even with a potential outcome measure that would be sensitive enough to determine disease progression and, thus, the efficacy or failure of a disease-modifying treatment, the question of clinical relevance remains unanswered. In this systematic review, we analyzed outcome measures and definitions of disease progression in phase III clinical trials in primary and secondary progressive multiple sclerosis. We discuss advantages and disadvantages of clinical and paraclinical outcome measures aiming for practical ways of combining them to detect disability progression more sensitively both in future clinical trials and current clinical routine.
Inhibition of UBA5 Expression and Induction of Autophagy in Breast Cancer Cells by Usenamine A
Authors: Fang Bo , Li Zijun , Qiu Yinda , Cho Namki , Yoo Hee Min
Published: September 2021

Breast cancer is now the most common type of cancer worldwide, surpassing lung cancer. This issue is further worsened by the lack of effective therapies for the disease. Recent reports indicate that the inhibition of ubiquitin-like modifier-activating enzyme 5 (UBA5) can impede tumor development. However, there have been few reports regarding UBA5-inhibiting compounds. This work studied usenamine A, a natural product from the lichen Usnea longissimi that exhibits UBA5-inhibitory effects. Bioinformatics analysis was performed using public databases, and the anti-proliferative ability of usenamine A in breast cancer cells was examined through MTS and colony formation assays. Flow cytometry and western blot analysis were also conducted to examine and analyze cell cycle arrest and apoptosis. In addition, LC3B-RFP and UBA5 expression plasmids were used for the analysis of usenamine A-induced autophagy. According to the bioinformatics analysis results, UBA5 was upregulated in breast cancer. According to in vitro studies, usenamine A displayed prominent anti-proliferative activity and resulted in G2/M phase arrest in MDA-MB-231 cells. Moreover, usenamine A induced autophagy and endoplasmic reticulum stress in MDA-MB-231 cells. In conclusion, the findings support the potential of usenamine A as an agent that can attenuate the development and progression of breast cancer.
Dissecting Multiple Pathways in the Relaxation Dynamics of Helix <==> Coil Transitions with Optimum Dimensionality Reduction
Authors: Jas Gouri S. , Childs Ed W. , Middaugh C. Russell , Kuczera Krzysztof
Published: September 2021

Fast kinetic experiments with dramatically improved time resolution have contributed significantly to understanding the fundamental processes in protein folding pathways involving the formation of a-helices and b-hairpin, contact formation, and overall collapse of the peptide chain. Interpretation of experimental results through application of a simple statistical mechanical model was key to this understanding. Atomistic description of all events observed in the experimental findings was challenging. Recent advancements in theory, more sophisticated algorithms, and a true long-term trajectory made way for an atomically detailed description of kinetics, examining folding pathways, validating experimental results, and reporting new findings for a wide range of molecular processes in biophysical chemistry. This review describes how optimum dimensionality reduction theory can construct a simplified coarse-grained model with low dimensionality involving a kinetic matrix that captures novel insights into folding pathways. A set of metastable states derived from molecular dynamics analysis generate an optimally reduced dimensionality rate matrix following transition pathway analysis. Analysis of the actual long-term simulation trajectory extracts a relaxation time directly comparable to the experimental results and confirms the validity of the combined approach. The application of the theory is discussed and illustrated using several examples of helix <==> coil transition pathways. This paper focuses primarily on a combined approach of time-resolved experiments and long-term molecular dynamics simulation from our ongoing work.
Modelling Nonalcoholic Steatohepatitis In Vivo—A Close Transcriptomic Similarity Supports the Guinea Pig Disease Model
Authors: Skat-Rørdam Josephine , Ipsen David H. , Seemann Stefan E. , Latta Markus , Lykkesfeldt Jens , Tveden-Nyborg Pernille
Published: September 2021

The successful development of effective treatments against nonalcoholic steatohepatitis (NASH) is significantly set back by the limited availability of predictive preclinical models, thereby delaying and reducing patient recovery. Uniquely, the guinea pig NASH model develops hepatic histopathology and fibrosis resembling that of human patients, supported by similarities in selected cellular pathways. The high-throughput sequencing of guinea pig livers with fibrotic NASH (n = 6) and matched controls (n = 6) showed a clear separation of the transcriptomic profile between NASH and control animals. A comparison to NASH patients with mild disease (GSE126848) revealed a 45.2% overlap in differentially expressed genes, while pathway analysis showed a 34% match between the top 50 enriched pathways in patients with advanced NASH (GSE49541) and guinea pigs. Gene set enrichment analysis highlighted the similarity to human patients (GSE49541), also when compared to three murine models (GSE52748, GSE38141, GSE67680), and leading edge genes THRSP, CCL20 and CD44 were highly expressed in both guinea pigs and NASH patients. Nine candidate genes were identified as highly correlated with hepatic fibrosis (correlation coefficient > 0.8), and showed a similar expression pattern in NASH patients. Of these, two candidate genes (VWF and SERPINB9) encode secreted factors, warranting further investigations as potential biomarkers of human NASH progression. This study demonstrates key similarities in guinea pig and human NASH, supporting increased predictability when translating research findings to human patients.
Role of Calcium Homeostasis in Modulating EMT in Cancer
Authors: Jones Clark A. , Hazlehurst Lori A.
Published: September 2021

Calcium is essential for cells to perform numerous physiological processes. In cancer, the augmentation of calcium signaling supports the more proliferative and migratory cells, which is a characteristic of the epithelial-to-mesenchymal transition (EMT). By genetically and epigenetically modifying genes, channels, and entire signaling pathways, cancer cells have adapted to survive with an extreme imbalance of calcium that allows them to grow and metastasize in an abnormal manner. This cellular remodeling also allows for the evasion of immune surveillance and the development of drug resistance, which lead to poor prognosis in patients. Understanding the role calcium flux plays in driving the phenotypes associated with invasion, immune suppression, metastasis, and drug resistance remains critical for determining treatments to optimize clinical outcomes and future drug discovery.
Seasonal Variation of Antiretroviral Drug Exposure during the Year: The Experience of 10 Years of Therapeutic Drug Monitoring
Authors: Cusato Jessica , Mula Jacopo , Palermiti Alice , Manca Alessandra , Antonucci Miriam , Avataneo Valeria , De Vivo Elisa , Ianniello Alice , Calcagno Andrea , Di Perri Giovanni , De Nicolò Amedeo , D’Avolio Antonio
Published: September 2021

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved.
Sex Differences in Dopamine Receptors and Relevance to Neuropsychiatric Disorders
Authors: Williams Olivia O. F. , Coppolino Madeleine , George Susan R. , Perreault Melissa L.
Published: September 2021

Dopamine is an important neurotransmitter that plays a key role in neuropsychiatric illness. Sex differences in dopaminergic signaling have been acknowledged for decades and have been linked to sex-specific heterogeneity in both dopamine-related behaviours as well as in various neuropsychiatric disorders. However, the overall number of studies that have evaluated sex differences in dopamine signaling, both in health and in these disorders, is low. This review will bring together what is known regarding sex differences in innate dopamine receptor expression and function, as well as highlight the known sex-specific roles of dopamine in addiction, depression, anxiety, schizophrenia, and attention deficit hyperactivity disorder. Due to differences in prognosis, diagnosis, and symptomatology between male and female subjects in disorders that involve dopamine signaling, or in responses that utilize pharmacological interventions that target dopamine receptors, understanding the fundamental sex differences in dopamine receptors is of vital importance for the personalization of therapeutic treatment strategies.
Machine Learning Incorporating Host Factors for Predicting Survival in Head and Neck Squamous Cell Carcinoma Patients
Authors: Yu Han , Ma Sung Jun , Farrugia Mark , Iovoli Austin J. , Wooten Kimberly E. , Gupta Vishal , McSpadden Ryan P. , Kuriakose Moni A. , Markiewicz Michael R. , Chan Jon M. , Hicks Wesley L. , Platek Mary E. , Singh Anurag K.
Published: September 2021

Prognostication for cancer patients is integral for patient counseling and treatment planning, yet providing accurate prediction can be challenging using existing patient-specific clinical indicators and host factors. In this work, we evaluated common machine learning models in predicting head and neck squamous cell carcinoma (HNSCC) patients’ overall survival based on demographic, clinical features and host factors. We found random survival forest had best performance among the models evaluated, which achieved a C-index of 0.729 and AUROC of 0.792 in predicting two-year overall survival. In addition, we verified that host factors are independently predictive of HNSCC overall survival, which improved the C-index by a margin of 0.026 and the AUROC by 0.034. Due to the strong correlation among host factors, we showed that proper dimension reduction is an important step before their incorporation into the machine learning models, which provides a host factor score reflecting the patients’ nutrition and inflammation status. The score by itself showed excellent discriminating capacity with the high-risk group having a hazard ratio of 3.76 (1.93–7.32, p < 0.0001) over the low-risk group. The hazard ratios were further improved to 7.41 (3.66–14.98, p < 0.0001) by the random survival forest model after including demographic and clinical features.
A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling
Authors: Wu Alexander T. H. , Huang Hsu-Shan , Wen Ya-Ting , Lawal Bashir , Mokgautsi Ntlotlang , Huynh Thanh-Tuan , Hsiao Michael , Wei Li
Published: September 2021

Glioblastoma (GBM) is one of the most aggressive brain malignancies with high incidences of developing treatment resistance, resulting in poor prognoses. Glioma stem cell (GSC)-derived exosomes are important players that contribute to GBM tumorigenesis and aggressive properties. Herein, we investigated the inhibitory roles of GBM-N019, a novel small molecule on the transfer of aggressive and invasive properties through the delivery of oncogene-loaded exosomes from GSCs to naïve and non-GSCs. Our results indicated that GBM-N019 significantly downregulated the expressions of the mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and cyclin-dependent kinase 6 (CDK6) signaling networks with concomitant inhibitory activities against viability, clonogenicity, and migratory abilities of U251 and U87MG cells. Treatments with GBM-N019 halted the exosomal transfer of protein kinase B (Akt), mTOR, p-mTOR, and Ras-related protein RAB27A to the naïve U251 and U87MG cells, and rescued the cells from invasive and stemness properties that were associated with activation of these oncogenes. GBM-N019 also synergized with and enhanced the anti-GBM activities of palbociclib in vitro and in vivo. In conclusion, our results suggested that GBM-N019 possesses good translational relevance as a potential anti-glioblastoma drug candidate worthy of consideration for clinical trials against recurrent glioblastomas.
Assigning Co-Regulated Human Genes and Regulatory Gene Clusters
Authors: Strunz Tobias , Kellner Martin , Kiel Christina , Weber Bernhard H. F.
Published: September 2021

Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gene.
Regional Variation of Gap Junctional Connections in the Mammalian Inner Retina
Authors: Fusz Katalin , Kovács-Öller Tamás , Kóbor Péter , Szabó-Meleg Edina , Völgyi Béla , Buzás Péter , Telkes Ildikó
Published: September 2021

The retinas of many species show regional specialisations that are evident in the differences in the processing of visual input from different parts of the visual field. Regional specialisation is thought to reflect an adaptation to the natural visual environment, optical constraints, and lifestyle of the species. Yet, little is known about regional differences in synaptic circuitry. Here, we were interested in the topographical distribution of connexin-36 (Cx36), the major constituent of electrical synapses in the retina. We compared the retinas of mice, rats, and cats to include species with different patterns of regional specialisations in the analysis. First, we used the density of Prox1-immunoreactive amacrine cells as a marker of any regional specialisation, with higher cell density signifying more central regions. Double-labelling experiments showed that Prox1 is expressed in AII amacrine cells in all three species. Interestingly, large Cx36 plaques were attached to about 8–10% of Prox1-positive amacrine cell somata, suggesting the strong electrical coupling of pairs or small clusters of cell bodies. When analysing the regional changes in the volumetric density of Cx36-immunoreactive plaques, we found a tight correlation with the density of Prox1-expressing amacrine cells in the ON, but not in the OFF sublamina in all three species. The results suggest that the relative contribution of electrical synapses to the ON- and OFF-pathways of the retina changes with retinal location, which may contribute to functional ON/OFF asymmetries across the visual field.