bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Dog-Assisted Therapies on Cognitive Mnemonic Capabilities in People Affected by Alzheimer’s Disease
Authors: Quintavalla Fausto , Cao Simona , Spinelli Diana , Caffarra Paolo , Rossi Fiammetta M. , Basini Giuseppina , Sabbioni Alberto
Published: May 2021

Alzheimer’s disease (AD) is the most common cause of dementia in humans and, currently, a valid treatment is lacking. Our goal is to demonstrate the importance and benefits of the relationship with companion animals (considered as co-therapists), intended as a means of facilitating social relations and promoting evident wellbeing in AD patients. The study involved 30 randomly chosen patients with Alzheimer’s disease (group T) and three dogs. The group participated in a total of 24 animal-assisted interventions (AAIs) sessions over a span of 12 weeks, using the Mini-Mental State Examination (MMSE), Wellness and Cognitive Ability Questionnaire (Brief Assessment Cognition or BAC), and Alzheimer’s Disease Assessment Scale (ADAS) as assessment tests. A second group (group C), consisting of 10 people with AD, was enrolled as control group and underwent the same assessment tests but did not benefit from the presence of the dogs. Tests were carried out at time T0 (before starting sessions), T1 (end of sessions), and T2 (two months after last session). People belonging to group T achieved an overall improvement in their perceived state of wellbeing, even on a cognitive and mnemonic plane. However, two months after the end of the sessions, the test results in people suffering from AD decreased towards the baseline (T0). The study shows how such progress can be achieved through activities based on the relationship with an animal, as long as the animal is a steady presence in the life of the patient receiving the intervention. Dogs involved in other dog-assisted therapies have been found suitable also for assisting patients with AD.
Natural Endotoxemia in Dogs—A Hidden Condition That Can Be Treated with a Potential Probiotic Containing Bacillus subtilis, Bacillus licheniformis and Pediococcus acidilactici: A Study Model
Authors: Matei Maria-Catalina , Andrei Sanda Maria , Buza Victoria , Cernea Mihai Sorin , Dumitras Daria Antonia , Neagu Daniela , Rafa Horatiu , Popovici Cristian Paul , Szakacs Andrei Radu , Catinean Adrian , Stefanut Eugen , Stefanut Laura Cristina
Published: May 2021

Spore-based Bacillus spp. products are considered to have a higher probiotic potential compared to products containing only lactic acid bacteria because their viability in the gastrointestinal (GI) tract is higher, even when GI environmental conditions are unfavorable. The aim of this study was to assess the effect of a Bacillus subtilis, Bacillus licheniformis and Pediococcus acidilactici spore-based potential probiotic on the natural levels of postprandial endotoxemia. A total of 11 dogs completed the study: group 1—healthy dogs: n = 5; group 2—dogs with apparent dysbiosis: n = 6. For 30 days, the dogs were fed the probiotic product; clinical examinations and blood sampling were done before and after completion of the probiotic treatment. Endotoxin levels were assessed pre-meal, 6 h and 12 h post-meal, before initiation and after completion of the treatment. The results showed a decrease in endotoxin levels after treatment, especially 12 h post-meal (group 1: 20.60%; group 2: 44.93%). This study reports new information with regard to natural endotoxemia levels in dogs and suggests that a multi-strain formula (spore-based) consisting of B. subtilis, B. licheniformis and P. acidilactici is able to diminish endotoxin values.
Coenzyme Q10 and Immune Function: An Overview
Authors: Mantle David , Heaton Robert A. , Hargreaves Iain P.
Published: May 2021

Coenzyme Q10 (CoQ10) has a number of important roles in the cell that are required for optimal functioning of the immune system. These include its essential role as an electron carrier in the mitochondrial respiratory chain, enabling the process of oxidative phosphorylation to occur with the concomitant production of ATP, together with its role as a potential lipid-soluble antioxidant, protecting the cell against free radical-induced oxidation. Furthermore, CoQ10 has also been reported to have an anti-inflammatory role via its ability to repress inflammatory gene expression. Recently, CoQ10 has also been reported to play an important function within the lysosome, an organelle central to the immune response. In view of the differing roles CoQ10 plays in the immune system, together with the reported ability of CoQ10 supplementation to improve the functioning of this system, the aim of this article is to review the current literature available on both the role of CoQ10 in human immune function and the effect of CoQ10 supplementation on this system.
A Multi-Channel and Multi-Spatial Attention Convolutional Neural Network for Prostate Cancer ISUP Grading
Authors: Yang Bochen , Xiao Zhifeng
Published: May 2021

Prostate cancer (PCa) is one of the most prevalent cancers worldwide. As the demand for prostate biopsies increases, a worldwide shortage and an uneven geographical distribution of proficient pathologists place a strain on the efficacy of pathological diagnosis. Deep learning (DL) is able to automatically extract features from whole-slide images of prostate biopsies annotated by skilled pathologists and to classify the severity of PCa. A whole-slide image of biopsies has many irrelevant features that weaken the performance of DL models. To enable DL models to focus more on cancerous tissues, we propose a Multi-Channel and Multi-Spatial (MCMS) Attention module that can be easily plugged into any backbone CNN to enhance feature extraction. Specifically, MCMS learns a channel attention vector to assign weights to channels in the feature map by pooling from multiple attention branches with different reduction ratios; similarly, it also learns a spatial attention matrix to focus on more relevant areas of the image, by pooling from multiple convolutional layers with different kernel sizes. The model is verified on the most extensive multi-center PCa dataset that consists of 11,000 H&E-stained histopathology whole-slide images. Experimental results demonstrate that an MCMS-assisted CNN can effectively boost prediction performance in accuracy (ACC) and quadratic weighted kappa (QWK), compared with prior studies. The proposed model and results can serve as a credible benchmark for future research in automated PCa grading.
Effect of Harmonics on Ferroresonance in Low Voltage Power Factor Correction System—A Case Study
Authors: Kutija Martina , Pravica Luka
Published: May 2021

This paper presents a case study of three-phase ferroresonance in a low-voltage power factor correction system and investigates the influence of harmonic distortion on the occurrence of ferroresonance. Ferroresonance is an extremely dangerous and rare phenomenon that causes overvoltages and overcurrents in the system and degrades the power quality. The study is carried out on real field measurements in an industrial plant where ferroresonance occurs in the power factor correction (PFC) system at the detuned reactor. The three-phase ferroresonance analysed in this paper is an extremely rare phenomenon that has never been reported in this type of configuration. The measurement results have shown that in this type of configuration the high harmonic distortion is a necessary condition for ferroresonance to occur. In such conditions, switching on the capacitor stage triggers the ferroresonance with quasi-periodic oscillations supported by the medium voltage grid. The main contribution is the analysis of the three-phase ferroresonance in the detuned PFC system and the influence of the harmonics on the occurrence of the ferroresonance in such a case. The possible solutions to this problem and recommendations to avoid this phenomenon are discussed.
Methodological and On-Site Applied Construction Layout Plan with Batter Boards Stake-Out Methods Comparison: A Case Study of Romania
Authors: Sestras Paul
Published: May 2021

The layout or stake-out is one of the most important assignments of the surveying engineer, and it is of vital importance in the building process, as the designed geometries of the structure ensure the verticality and the correct positioning inside the terrain. The mission of the surveying engineer involves both legal and technical aspects, and the correct planning of the layout process must take into consideration aspects regarding the site conditions, instrumentation used, the required and achievable accuracies, network design and survey methods used. Given the vast applications of geodesy and topography in different domains and industries, the study incorporates general notions and technical aspects regarding the workflow in cadastre and construction surveying, guidelines for an efficient design of site layout plan with on-site applicability, as well as a novel comparison between four methods of construction lines geometry layout on batter boards. The results of this study aim to further consolidate the importance of accurate and efficient construction layout projects, with comprehensive design plans, methods and instrumentation selection, as well as recommendations. The presented discussions and conclusions are of interest to the geodetic community as well as the construction industry, and due to the pragmatic and experimental nature of the research, incorporates technical notes and original results of professional and academic importance.
Semantic Structure from Motion for Railroad Bridges Using Deep Learning
Authors: Park Gun , Lee Jae Hyuk , Yoon Hyungchul
Published: May 2021

Current maintenance practices consume significant time, cost, and manpower. Thus, a new technique for maintenance is required. Construction information technologies, including building information modeling (BIM), have recently been applied to the field to carry out systematic and productive planning, design, construction, and maintenance. Although BIM is increasingly being applied to new structures, its application to existing structures has been limited. To apply BIM to an existing structure, a three-dimensional (3D) model of the structure that accurately represents the as-is status should be constructed and each structural component should be specified manually. This study proposes a method that constructs a 3D model and specifies the structural component automatically using photographic data with a camera installed on an unmanned aerial vehicle. This procedure is referred to as semantic structure from motion because it constructs a 3D point cloud model together with semantic information. A validation test was carried out on a railroad bridge to validate the performance of the proposed system. The average precision, intersection over union, and BF scores were 80.87%, 66.66%, and 56.33%, respectively. The proposed method could improve the current scan-to-BIM procedure by generating the as-is 3D point cloud model by specifying the structural component automatically.
Combination of Dual-Energy X-ray Transmission and Variable Gas-Ejection for the In-Line Automatic Sorting of Many Types of Scrap in One Measurement
Authors: Xiong Tianzhong , Ye Wenhua , Xu Xiang
Published: May 2021

As an important part of pretreatment before recycling, sorting has a great impact on the quality, efficiency, cost and difficulty of recycling. In this paper, dual-energy X-ray transmission (DE-XRT) combined with variable gas-ejection is used to improve the quality and efficiency of in-line automatic sorting of waste non-ferrous metals. A method was proposed to judge the sorting ability, identify the types, and calculate the mass and center-of-gravity coordinates according to the shading of low-energy, the line scan direction coordinate and transparency natural logarithm ratio of low energy to high energy (R_value). The material identification was satisfied by the nearest neighbor algorithm of effective points in the material range to the R_value calibration surface. The flow-process of identification was also presented. Based on the thickness of the calibration surface, the material mass and center-of-gravity coordinates were calculated. The feasibility of controlling material falling points by variable gas-ejection was analyzed. The experimental verification of self-made materials showed that identification accuracy by count basis was 85%, mass and center-of-gravity coordinates calculation errors were both below 5%. The method proposed features high accuracy, high efficiency, and low operation cost and is of great application value even to other solid waste sorting, such as plastics, glass and ceramics.
Performance Evaluation of RNN with Hyperbolic Secant in Gate Structure through Application of Parkinson’s Disease Detection
Authors: Fujita Tomohiro , Luo Zhiwei , Quan Changqin , Mori Kohei , Cao Sheng
Published: May 2021

This paper studies a novel recurrent neural network (RNN) with hyperbolic secant (sech) in the gate for a specific medical application task of Parkinson’s disease (PD) detection. In detail, it focuses on the fact that patients with PD have motor speech disorders, by converting the voice data into black-and-white images of a recurrence plot (RP) at specific time intervals and constructing the detection model that combines RNN and convolutional neural network (CNN); the study evaluates the performance of the RNN with sech gate compared with long short-term memory (LSTM) and gated recurrent unit (GRU) with conventional gates. As a result, the proposed model obtained similar results to LSTM and GRU (an average accuracy of about 70%) with less hyperparameters, resulting in faster learning. In addition, in the framework of the RNN with sech in gate, the accuracy obtained by using tanh as the output activation function is higher than using the relu function. The proposed method will see more improvement by increasing the data in the future. More analysis on the input sound type, the RP image size, and the deep learning structures will be included in our future work for further improving the performance of PD detection from voice.
Curve-Localizability-SVM Active Localization Research for Mobile Robots in Outdoor Environments
Authors: Gong Liang , Yu Xiangyu , Wang Jingchuan
Published: May 2021

Working environment of mobile robots has gradually expanded from indoor structured scenes to outdoor scenes such as wild areas in recent years. The expansion of application scene, change of sensors and the diversity of working tasks bring greater challenges and higher demands to active localization for mobile robots. The efficiency and stability of traditional localization strategies in wild environments are significantly reduced. On the basis of considering features of the environment and the robot motion curved surface, this paper proposes a curve-localizability-SVM active localization algorithm. Firstly, we present a curve-localizability-index based on 3D observation model, and then based on this index, a curve-localizability-SVM path planning strategy and an improved active localization method are proposed. Obtained by setting the constraint space and objective function of the planning algorithm, where curve-localizability is the main constraint, the path helps improve the convergence speed and stability in complex environments of the active localization algorithm. Helped by SVM, the path is smoother and safer for large robots. The algorithm was tested by comparative experiments and analysis in real environment and robot platform, which verified the improvement of efficiency and stability of the new strategy.
A Comparative Performance Evaluation of Routing Protocols for Flying Ad-Hoc Networks in Real Conditions
Authors: Guillen-Perez Antonio , Montoya Ana-Maria , Sanchez-Aarnoutse Juan-Carlos , Cano Maria-Dolores
Published: May 2021

Unmanned aerial vehicles (UAVs) are widely used in our modern society and their development is rapidly accelerating. Flying Ad Hoc Networks (FANETs) have opened a new window of opportunity to create new value-added services. However, the characteristics that make FANETs unique, such as node mobility, node distance, energy constraints, etc., imply that several guidelines need to be considered for their successful deployment. Although numerous routing protocols have been proposed for FANETs, due to the wide range of applications in which FANETs can be applied, not all routing protocols can be used. Due to this challenge, after breaking down and classifying the different types of existing routing protocols for FANET, this paper analyzes and compares the performance of several routing protocols (Babel, BATMAN-ADV, and OLSR) in terms of throughput and packet loss in a real deployment composed of several UAV nodes using 2.4 and 5 GHz WiFi networks. The results show that Babel achieves better performance in the studied metrics than OLSR and BATMAN-ADV, while BATMAN-ADV delivers significantly lower performance. This experimental study confirms the importance of choosing the proper routing protocol for FANETs and their performance evaluation, something that will be extremely important in a few years when this type of network will be common in our day-to-day life.
Complementary Substrates-Brewery Wastewater and Piggery Effluent—Assessment and Microbial Community Profiling in a Hybrid Anaerobic Reactor
Authors: Eusébio Ana , Neves André , Marques Isabel Paula
Published: May 2021

A hybrid anaerobic reactor was operated under the complementary effluents concept to reduce the unbalanced/inhibitory capacity of the provided piggery effluent. Brewery wastewater was chosen to complement piggery effluent (60:40% v/v, respectively). The HRT reduction from 6.7 to 3.0 days allowed the testing of an organic load increase from 4.5 to 10.0 g COD/L·d, which resulted in the almost doubling of biogas production. Biogas volumes (1.2 and 2.1 L/L·d, respectively) associated with its quality (>77% CH4) revealed that the hybrid anaerobic reactor responded positively to the operational changes and that piggery effluent can be advantageously digested using the brewery wastewater as the complementary effluent. The unit bottom and the packing bed were the main functional sections recognized in the hybrid. At the beginning of anaerobic digestion, bacterial populations belonged mostly to Bacteroidales (33%) and Clostridiales (35%). The process stability and the biogas quality at 3-d HRT were related to a change in the structure composition, since Flavobacteriales (18%), Bacillales (7%), Pseudomonadales (11%) and members of the Alcaligenaceae family (5%) also integrated the microbial communities. An evident change had also occurred in archaeal populations at this phase. Methanosaeta became the dominant genus (95%), confirming that acetoclastic methanogenesis was the main way for methane production.
The Role of Physical Parameterizations on the Numerical Weather Prediction: Impact of Different Cumulus Schemes on Weather Forecasting on Complex Orographic Areas
Authors: Castorina Giuseppe , Caccamo Maria Teresa , Colombo Franco , Magazù Salvatore
Published: May 2021

Numerical weather predictions (NWP) play a fundamental role in air quality management. The transport and deposition of all the pollutants (natural and/or anthropogenic) present in the atmosphere are strongly influenced by meteorological conditions such as, for example, precipitation and winds. Furthermore, the presence of particulate matter in the atmosphere favors the physical processes of nucleation of the hydrometeors, thus increasing the risk of even extreme weather events. In this framework of reference, the present work aimed to improve the quality of weather forecasts related to extreme events through the optimization of the weather research and forecasting (WRF) model. For this purpose, the simulation results obtained using the WRF model, where physical parametrizations of the cumulus scheme can be optimized, are reported. As a case study, we considered the extreme meteorological event recorded on 25 November 2016, which affected the whole territory of Sicily and, in particular, the area of Sciacca (Agrigento). In order, to evaluate the performance of the proposed approach, we compared the WRF model outputs with data obtained by a network of radar and weather stations. The comparison was performed through statistical methods on the basis of a “contingency table”, which allowed for ascertaining the best suited physical parametrizations able to reproduce this event.
The Modulation Effect on the ELVEs and Sprite Halos by Concentric Gravity Waves Based on the Electromagnetic Pulse Coupled Model
Authors: Wang Chao , Wen Ying , Zhang Jinbo , Zhang Qilin , Qiu Juwei
Published: May 2021

By employing the finite-difference time-domain method, the processes of electric field variation and morphological development of the optical radiation field of ELVEs and sprite halos were simulated in this article. Simulations of ELVEs show two optical radiation field centers, with a concentrated luminous zone from 85 to 100 km and an inner weaker optical radiation center. The electric field exhibits an obvious sparse and dense ripple pattern induced by the concentric gravity waves (CGWs) at altitudes of 90–100 km, which mainly occurs during the decline period of electric field with a shallow steepness. The alternating distance of the variations in the sparse and dense patterns is about 40 km, which corresponds to the horizontal wavelength of the electric field. The CGWs induce significant deformation of the inner optical radiation field, even splitting into multiple luminous regions. Simulations of sprite halos indicate that the horizontal range of the electrical field generated by lightning current is within 50 km, and a strong local electric field formed in the region right above the lightning channel is due to the small-scale breakdown current. Thus, the increased electron density shields the upper regions and reduces the electrical field’s strength. The sprite halos luminous zone is pancake-shaped, and it originates at 85 km along with a downward developing trend. The disturbance of sprite halos’ luminescence caused by CGWs mainly occurs at about 80–100 km directly above the lightning channel, and the primary deformation zone is located within 30 km of the lightning channel, which is also the region with the most recognizable electric field disturbance.
Development and Evaluation of SLINE 1.0, a Line Source Dispersion Model for Gaseous Pollutants by Incorporating Wind Shear Near the Ground under Stable and Unstable Atmospheric Conditions
Authors: Madiraju Saisantosh Vamshi Harsha , Kumar Ashok
Published: May 2021

Transportation sources are a major contributor to air pollution in urban areas, and the role of air quality modeling is vital in the formulation of air pollution control and management strategies. Many models have appeared in the literature to estimate near-field ground level concentrations from mobile sources moving on a highway. However, current models do not account explicitly for the effect of wind shear (magnitude) near the ground while computing the ground level concentrations near highways from mobile sources. This study presents an analytical model (SLINE 1.0) based on the solution of the convective–diffusion equation by incorporating the wind shear near the ground for gaseous pollutants. The dispersion coefficients for stable and unstable atmospheric conditions are based on the near-field parameterization. Initial vertical dispersion coefficient due to the wake effect of mobile sources is incorporated based on a literature review. The model inputs include emission factor, wind speed, wind direction, turbulence parameters, and terrain features. The model is evaluated based on the Idaho Falls field study (2008). The performance of the model is evaluated using several statistical parameters. Results indicate that the model performs well against this dataset in predicting concentrations under both the stable and unstable atmospheric conditions. The sensitivity of the model to compute ground-level concentrations for different inputs is presented for three different downwind distances. In general, the model shows Type III sensitivity (i.e., the errors in the input will show a corresponding change in the computed ground level concentrations) for most of the input variables using the ASTM (American Society for Testing and Materials) method. However, some recalibration of the model constants is needed using several field datasets to make sure that the model is acceptable for computing ground-level concentrations in engineering applications.
Photoionization Cross-Sections of Carbon-Like N+ Near the K-Edge (390–440 eV)
Authors: Mosnier Jean-Paul , Kennedy Eugene , Bizau Jean-Marc , Cubaynes Denis , Guilbaud Ségolène , Blancard Christophe , McLaughlin Brendan
Published: May 2021

High-resolution K-shell photoionization cross-sections for the C-like atomic nitrogen ion (N+) are reported in the 398 eV (31.15 Å) to 450 eV (27.55 Å) energy (wavelength) range. The results were obtained from absolute ion-yield measurements using the SOLEIL synchrotron radiation facility for spectral bandpasses of 65 meV or 250 meV. In the photon energy region 398–403 eV, 1s⟶2p autoionizing resonance states dominated the cross section spectrum. Analyses of the experimental profiles yielded resonance strengths and Auger widths. In the 415–440 eV photon region 1s⟶(1s2s22p2 4P)np and 1s⟶(1s2s22p2 2P)np resonances forming well-developed Rydberg series up n=7 and n=8 , respectively, were identified in both the single and double ionization spectra. Theoretical photoionization cross-section calculations, performed using the R-matrix plus pseudo-states (RMPS) method and the multiconfiguration Dirac-Fock (MCDF) approach were bench marked against these high-resolution experimental results. Comparison of the state-of-the-art theoretical work with the experimental studies allowed the identification of new resonance features. Resonance strengths, energies and Auger widths (where available) are compared quantitatively with the theoretical values. Contributions from excited metastable states of the N+ ions were carefully considered throughout.
Adipose-Derived Mesenchymal Stem Cells (AD-MSCs) against Ultraviolet (UV) Radiation Effects and the Skin Photoaging
Authors: Gentile Pietro , Garcovich Simone
Published: May 2021

The skin is a natural barrier against the ultraviolet (UV) radiation of sunlight. The long-term and/or repetitive exposure to the sunlight and related UV radiation may change the skin structure, decreasing collagen production, promoting premature skin aging, which is termed “photoaging”. The signs of photoaging include wrinkle formation, mottled pigmentation, and/or cancerous changes. For many years, adipose-derived mesenchymal stem cells (AD-MSCs) and fat grafting (F-GRF) have been used to combat photoaging signs, wrinkles, loss of elasticity, and face soft tissue defects. Several studies have analyzed in vitro actions of AD-MSCs against photoaging’s effects, thanks to their migratory activity, paracrine actions, and related in vivo–ex vivo outcomes. In fact, AD-MSCs act against skin photoaging in vitro via activation of dermal fibroblast proliferation, antioxidant effect, and matrix metalloproteinases (MMPs) reduction. In vivo and ex vivo outcomes regard the local injection of AD-MSCs, F-GRF, and/or enriched-F-GRF with AD-MSCs directly in the wrinkles and the face’s soft tissue defects. This concise review summarizes the most recent in vitro, in vivo and ex vivo outcomes and developments on the effects of AD-MSCs and F-GRF against photoaging.
Endocan and Circulating Progenitor Cells in Women with Systemic Sclerosis: Association with Inflammation and Pulmonary Hypertension
Authors: Lo Gullo Alberto , Mandraffino Giuseppe , Rodríguez-Carrio Javier , Scuruchi Michele , Sinicropi Davide , Postorino Maria , Morace Carmela , Giuffrida Clemente , Sciortino Davide , Gallizzi Romina , Loddo Saverio , Zito Concetta , Squadrito Giovanni
Published: May 2021

Background: Systemic sclerosis (SSc) is characterized by early vasculopathy and fibrosis in the skin, lungs, and other tissues. Vascular manifestations of SSc include Raynaud’s phenomenon, digital ulcers, and pulmonary artery hypertension (PAH). PAH is the second most common cause of mortality in SSc. Circulating CD34+ cells associated with cardiovascular health status in several conditions, including chronic immune-inflammatory disease. CD34+ cell numbers have been found inconstantly reduced in SSc. Endocan, a proteoglycan expressed by endothelial cells, was recently suggested as a marker of vascular stress. We tested the relationships among CD34+ cells, endocan, inflammatory markers, vitamin D levels, and clinical parameters in SSc patients with PAH. METHODS: Standard echocardiography was performed. Vitamin D levels, CD34+ cells, inflammatory markers, endocan plasma levels were determined in 36 female SSc patients (24 diffuse/12 limited) and 36 matched controls (HC). RESULTS: We found no difference in CD34+ and vitamin D levels in SSc as compared to controls; ESR, CRP, fibrinogen, endocan, sPAP were higher in SSc with respect to controls. We found a correlation between endocan and: CD34+ cells (r: −0.540, p = 0.002), pulmonary arterial pressure (sPAP) (r: 0.565, p < 0.001), tricuspid annular plane excursion (TAPSE) (r: −0.311, p < 0.01), and E/A ratio (r: −0.487, p < 0.001), but not with ejection fraction (r: −0.057, p = 0.785) in SSc. CD34+ cells correlate with fibrinogen (r: −0.619, p < 0.001), sPAP (r: −0.404, p = 0.011), E/A (r: 0.470, p < 0.005 in SSc. CONCLUSION: CD34+ cell number was significantly correlated with endocan levels and with sPAP in SSc; endocan and CD34+ progenitor cells might be suggested as a potential marker of disease status.
Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia
Authors: Fullam Timothy , Statland Jeffrey
Published: May 2021

Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early phases of disease remains challenging. While no single clinical or diagnostic tests is specific, there are several developing biomarkers and neuroimaging technologies which may help distinguish PLS from HSP and UMNdALS. Recent consensus diagnostic criteria and use of evolving technologies will allow more precise delineation of PLS from other upper motor neuron disorders and aid in the targeting of potentially disease-modifying therapeutics.
Design and Implementation of an EEG-Based Learning-Style Recognition Mechanism
Authors: Zhang Bingxue , Chai Chengliang , Yin Zhong , Shi Yang
Published: May 2021

Existing methods for learning-style recognition are highly subjective and difficult to implement. Therefore, the present study aimed to develop a learning-style recognition mechanism based on EEG features. The process for the mechanism included labeling learners’ actual learning styles, designing a method to effectively stimulate different learners’ internal state differences regarding learning styles, designing the data-collection method, designing the preprocessing procedure, and constructing the recognition model. In this way, we designed and verified an experimental method that can effectively stimulate learning-style differences in the information-processing dimension. In addition, we verified the effectiveness of using EEG signals to recognize learning style. The recognition accuracy of the learning-style processing dimension was 71.2%. This result is highly significant for the further exploration of using EEG signals for effective learning-style recognition.
Ultrasonic Vocalizations Emission across Development in Rats: Coordination with Respiration and Impact on Brain Neural Dynamics
Authors: Boulanger-Bertolus Julie , Mouly Anne-Marie
Published: May 2021

Rats communicate using ultrasonic vocalizations (USV) throughout their life when confronted with emotionally stimulating situations, either negative or positive. The context of USV emission and the psychoacoustic characteristics of the vocalizations change greatly between infancy and adulthood. Importantly, the production of USV is tightly coordinated with respiration, and respiratory rhythm is known to influence brain activity and cognitive functions. This review goes through the acoustic characteristics and mechanisms of production of USV both in infant and adult rats and emphasizes the tight relationships that exist between USV emission and respiration throughout the rat’s development. It further describes how USV emission and respiration collectively affect brain oscillatory activities. We discuss the possible association of USV emission with emotional memory processes and point out several avenues of research on USV that are currently overlooked and could fill gaps in our knowledge.
Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies
Authors: Hinterleitner Martina , Sipos Bence , Wagner Verena , Grottenthaler Julia M. , Lauer Ulrich M. , Zender Lars , Hinterleitner Clemens
Published: May 2021

Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.
AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review
Authors: Hinz Nico , Jücker Manfred
Published: May 2021

Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.
CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development
Authors: Hashimoto Kenji
Published: May 2021

Immune checkpoint inhibitors have altered the treatment landscape significantly in several cancers, yet not enough for many cancer patients. T cell costimulatory receptors have been pursued as targets for the next generation of cancer immunotherapies, however, sufficient clinical efficacy has not yet been achieved. CD137 (TNFRSF9, 4-1BB) provides co-stimulatory signals and activates cytotoxic effects of CD8+ T cells and helps to form memory T cells. In addition, CD137 signalling can activate NK cells and dendritic cells which further supports cytotoxic T cell activation. An agonistic monoclonal antibody to CD137, urelumab, provided promising clinical efficacy signals but the responses were achieved above the maximum tolerated dose. Utomilumab is another CD137 monoclonal antibody to CD137 but is not as potent as urelumab. Recent advances in antibody engineering technologies have enabled mitigation of the hepato-toxicity that hampered clinical application of urelumab and have enabled to maintain similar potency to urelumab. Next generation CD137 targeting molecules currently in clinical trials support T cell and NK cell expansion in patient samples. CD137 targeting molecules in combination with checkpoint inhibitors or ADCC-enhancing monoclonal antibodies have been sought to improve both clinical safety and efficacy. Further investigation on patient samples will be required to provide insights to understand compensating pathways for future combination strategies involving CD137 targeting agents to optimize and maintain the T cell activation status in tumors.
Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors
Authors: Idlas Pierre , Lepeltier Elise , Jaouen Gérard , Passirani Catherine
Published: May 2021

Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens. Lipid nanocapsules (LNCs), meanwhile, are nanoparticles obtained by a free organic solvent process. LNCs consist of an oily core surrounded by amphiphilic surfactants and are perfectly adapted to encapsulate these hydrophobic compounds. The different in vitro and in vivo experiments performed with this ferrocifen-loaded nanocarrier have revealed promising results in several multidrug-resistant cancer cell lines such as glioblastoma, breast cancer and metastatic melanoma, alone or in combination with other therapies. This review provides an exhaustive summary of the use of ferrocifen-loaded LNCs as a promising nanomedicine, outlining the ferrocifen mechanisms of action on cancer cells, the nanocarrier formulation process and the in vivo results obtained over the last two decades.
Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model
Authors: Qin Shuyang S. , Han Booyeon J. , Williams Alyssa , Jackson Katherine M. , Jewell Rachel , Chacon Alexander C. , Lord Edith M. , Linehan David C. , Kim Minsoo , Reuben Alexandre , Gerber Scott A. , Prieto Peter A.
Published: May 2021

Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.
Early Prediction of Breast Cancer Recurrence for Patients Treated with Neoadjuvant Chemotherapy: A Transfer Learning Approach on DCE-MRIs
Authors: Comes Maria Colomba , La Forgia Daniele , Didonna Vittorio , Fanizzi Annarita , Giotta Francesco , Latorre Agnese , Martinelli Eugenio , Mencattini Arianna , Paradiso Angelo Virgilio , Tamborra Pasquale , Terenzio Antonella , Zito Alfredo , Lorusso Vito , Massafra Raffaella
Published: May 2021

Cancer treatment planning benefits from an accurate early prediction of the treatment efficacy. The goal of this study is to give an early prediction of three-year Breast Cancer Recurrence (BCR) for patients who underwent neoadjuvant chemotherapy. We addressed the task from a new perspective based on transfer learning applied to pre-treatment and early-treatment DCE-MRI scans. Firstly, low-level features were automatically extracted from MR images using a pre-trained Convolutional Neural Network (CNN) architecture without human intervention. Subsequently, the prediction model was built with an optimal subset of CNN features and evaluated on two sets of patients from I-SPY1 TRIAL and BREAST-MRI-NACT-Pilot public databases: a fine-tuning dataset (70 not recurrent and 26 recurrent cases), which was primarily used to find the optimal subset of CNN features, and an independent test (45 not recurrent and 17 recurrent cases), whose patients had not been involved in the feature selection process. The best results were achieved when the optimal CNN features were augmented by four clinical variables (age, ER, PgR, HER2+), reaching an accuracy of 91.7% and 85.2%, a sensitivity of 80.8% and 84.6%, a specificity of 95.7% and 85.4%, and an AUC value of 0.93 and 0.83 on the fine-tuning dataset and the independent test, respectively. Finally, the CNN features extracted from pre-treatment and early-treatment exams were revealed to be strong predictors of BCR.
Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models
Authors: Benedicto Ignacio , Dorado Beatriz , Andrés Vicente
Published: May 2021

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that recapitulates many symptoms of physiological aging and precipitates death. Patients develop severe vascular alterations, mainly massive vascular smooth muscle cell loss, vessel stiffening, calcification, fibrosis, and generalized atherosclerosis, as well as electrical, structural, and functional anomalies in the heart. As a result, most HGPS patients die of myocardial infarction, heart failure, or stroke typically during the first or second decade of life. No cure exists for HGPS, and therefore it is of the utmost importance to define the mechanisms that control disease progression in order to develop new treatments to improve the life quality of patients and extend their lifespan. Since the discovery of the HGPS-causing mutation, several animal models have been generated to study multiple aspects of the syndrome and to analyze the contribution of different cell types to the acquisition of the HGPS-associated cardiovascular phenotype. This review discusses current knowledge about cardiovascular features in HGPS patients and animal models and the molecular and cellular mechanisms through which progerin causes cardiovascular disease.
A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease
Authors: Pitt Ashley S. , Buchanan Susan K.
Published: May 2021

The central role mitochondria play in cellular homeostasis has made its study critical to our understanding of various aspects of human health and disease. Mitochondria rely on the translocase of the outer membrane (TOM) complex for the bulk of mitochondrial protein import. In addition to its role as the major entry point for mitochondrial proteins, the TOM complex serves as an entry pathway for viral proteins. TOM complex subunits also participate in a host of interactions that have been studied extensively for their function in neurodegenerative diseases, cardiovascular diseases, innate immunity, cancer, metabolism, mitophagy and autophagy. Recent advances in our structural understanding of the TOM complex and the protein import machinery of the outer mitochondrial membrane have made structure-based therapeutics targeting outer mitochondrial membrane proteins during mitochondrial dysfunction an exciting prospect. Here, we describe advances in understanding the TOM complex, the interactome of the TOM complex subunits, the implications for the development of therapeutics, and our understanding of the structure/function relationship between components of the TOM complex and mitochondrial homeostasis.
Dissecting the RecA-(In)dependent Response to Mitomycin C in Mycobacterium tuberculosis Using Transcriptional Profiling and Proteomics Analyses
Authors: Brzostek Anna , Płociński Przemysław , Minias Alina , Ciszewska Aneta , Gąsior Filip , Pawełczyk Jakub , Dziadek Bożena , Słomka Marcin , Dziadek Jarosław
Published: May 2021

Mycobacteria exploit at least two independent global systems in response to DNA damage: the LexA/RecA-dependent SOS response and the PafBC-regulated pathway. Intracellular pathogens, such as Mycobacterium tuberculosis, are exposed to oxidative and nitrosative stress during the course of infection while residing inside host macrophages. The current understanding of RecA-independent responses to DNA damage is based on the saprophytic model of Mycobacterium smegmatis, a free-living and nonpathogenic mycobacterium. The aim of the present study was to identify elements of RecA-independent responses to DNA damage in pathogenic intracellular mycobacteria. With the help of global transcriptional profiling, we were able to dissect RecA-dependent and RecA-independent pathways. We profiled the DNA damage responses of an M. tuberculosis strain lacking the recA gene, a strain with an undetectable level of the PafBC regulatory system, and a strain with both systems tuned down simultaneously. RNA-Seq profiling was correlated with the evaluation of cell survival in response to DNA damage to estimate the relevance of each system to the overall sensitivity to genotoxic agents. We also carried out whole-cell proteomics analysis of the M. tuberculosis strains in response to mitomycin C. This approach highlighted that LexA, a well-defined key element of the SOS system, is proteolytically inactivated during RecA-dependent DNA repair, which we found to be transcriptionally repressed in response to DNA-damaging agents in the absence of RecA. Proteomics profiling revealed that AlkB was significantly overproduced in the ΔrecA pafBCCRISPRi/dCas9 strain and that Holliday junction resolvase RuvX was a DNA damage response factor that was significantly upregulated regardless of the presence of functional RecA and PafBC systems, thus falling into a third category of DNA damage factors: RecA- and PafBC-independent. While invisible to the mass spectrometer, the genes encoding alkA, dnaB, and dnaE2 were significantly overexpressed in the ΔrecA pafBCCRISPRi/dCas9 strain at the transcript level.