bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction and Diagnosis of Respiratory Disease by Combining Convolutional Neural Network and Bi-directional Long Short-Term Memory Methods
Authors: Li Li , Ayiguli Alimu , Luan Qiyun , Yang Boyi , Subinuer Yilamujiang , Gong Hui , Zulipikaer Abudureherman , Xu Jingran , Zhong Xuemei , Ren Jiangtao , Zou Xiaoguang
Published: May 2022

Objective

Based on the respiratory disease big data platform in southern Xinjiang, we established a model that predicted and diagnosed chronic obstructive pulmonary disease, bronchiectasis, pulmonary embolism and pulmonary tuberculosis, and provided assistance for primary physicians.

Methods

The method combined convolutional neural network (CNN) and long-short-term memory network (LSTM) for prediction and diagnosis of respiratory diseases. We collected the medical records of inpatients in the respiratory department, including: chief complaint, history of present illness, and chest computed tomography. Pre-processing of clinical records with “jieba” word segmentation module, and the Bidirectional Encoder Representation from Transformers (BERT) model was used to perform word vectorization on the text. The partial and total information of the fused feature set was encoded by convolutional layers, while LSTM layers decoded the encoded information.

Results

The precisions of traditional machine-learning, deep-learning methods and our proposed method were 0.6, 0.81, 0.89, and F1 scores were 0.6, 0.81, 0.88, respectively.

Conclusion

Compared with traditional machine learning and deep-learning methods that our proposed method had a significantly higher performance, and provided precise identification of respiratory disease.
Environmental Impact of Animal-Based Food Production and the Feasibility of a Shift Toward Sustainable Plant-Based Diets in the United States
Authors: Espinosa-Marrón Alan , Adams Kate , Sinno Lea , Cantu-Aldana Alejandra , Tamez Martha , Marrero Abrania , Bhupathiraju Shilpa N. , Mattei Josiemer
Published: May 2022

Evidence consistently suggests that plant-based diets promote human and planetary health. Reducing large-scale animal-based food production generates environmental benefits, as the entire livestock agriculture chain plays an outsized role in greenhouse gas emissions, land change and degradation, and scarcity-weighted water use. However, substituting animal products with their plant-based counterparts must come with consideration of the nutritional quality and resource usage of plant-based food production and processing operations. Several policy reforms have been implemented at the national, state, and municipal levels in the United States to support a transition toward more plant-based diets. Federal programs such as the Supplemental Nutrition Assistance Program and the Dietary Guidelines for Americans generally promote the consumption of unprocessed plant-based foods but include little to no information on sustainability and the harmful environmental impact of animal-based foods. National policies are complemented by state efforts aimed at incentivizing produce purchased from local suppliers and encouraging resource-conserving agriculture. At the local level, public schools are implementing programs to promote plant-based protein on their menus, and urban gardens are sprouting across the country to increase access to organic farming. This mini-review examines these policy reforms and behavioral intervention strategies, based on the social-ecological model, and discuss their capacity and limitations to promote a shift toward sustainably produced plant-based diets in the United States. We conclude that transforming the food systems toward plant-based diets in the animal-centered United States requires multi-sector collaboration and context-specific policy solutions to address diet-related climate concerns without neglecting health, social, and financial constraints.
Energy, Exergy, Entropy Generation Minimization, and Exergoenvironmental Analyses of Energy Systems-A Mini-Review
Authors: Ordonez Juan C. , Cavalcanti Eduardo J. C. , Carvalho Monica
Published: May 2022

Meeting the growing energy demands has become a crucial challenge, which should employ energy integration and benefit from the extraction of the maximum thermodynamic potential of the resources consumed. This brief review presents an overview of the essential elements of the methods of energy, exergy, entropy generation minimization, and exergoenvironmental analyses. In combination, these methodologies constitute a powerful toolbox for the design, analysis, and optimization of energy systems. The quantification of energy and environmental impacts provided by them is essential in guiding toward system designs that are consistent with current energy and environmental needs.
Hardware Security in Sensor and its Networks
Authors: Monjur Mohammad Mezanur Rahman , Heacock Joseph , Calzadillas Joshua , Mahmud MD Shaad , Roth John , Mankodiya Kunal , Sazonov Edward , Yu Qiaoyan
Published: May 2022

Sensor networks and IoT systems have been widely deployed in monitoring and controlling system. With its increasing utilization, the functionality and performance of sensor networks and their applications are not the only design aims; security issues in sensor networks attract more and more attentions. Security threats in sensor and its networks could be originated from various sectors: users in cyber space, security-weak protocols, obsolete network infrastructure, low-end physical devices, and global supply chain. In this work, we take one of the emerging applications, advanced manufacturing, as an example to analyze the security challenges in the sensor network. Presentable attacks—hardware Trojan attack, man-in-the-middle attack, jamming attack and replay attack—are examined in the context of sensing nodes deployed in a long-range wide-area network (LoRaWAN) for advanced manufacturing. Moreover, we analyze the challenges of detecting those attacks.
Endovascular Materials and Their Behavior in Peripheral Vascular Surgery
Authors: Mazzaccaro Daniela , Giannetta Matteo , Righini Paolo , Modafferi Alfredo , Malacrida Giovanni , Nano Giovanni
Published: May 2022

Endovascular techniques have progressively become the first option for the treatment of stenosis and occlusions of both aorto-iliac and femoro-popliteal district. The development of new technologies and new materials has broadened the applicability of the endovascular techniques, allowing the treatment of each lesion with the most suitable material. A knowledge of the behavior of endovascular materials when treating peripheral arterial disease (PAD) is, therefore, crucial for optimization of the results. Here, we aim to review the most important technical features of the actually available endovascular materials for treating PAD.
A Review of Modern Audio Deepfake Detection Methods: Challenges and Future Directions
Authors: Almutairi Zaynab , Elgibreen Hebah
Published: May 2022

A number of AI-generated tools are used today to clone human voices, leading to a new technology known as Audio Deepfakes (ADs). Despite being introduced to enhance human lives as audiobooks, ADs have been used to disrupt public safety. ADs have thus recently come to the attention of researchers, with Machine Learning (ML) and Deep Learning (DL) methods being developed to detect them. In this article, a review of existing AD detection methods was conducted, along with a comparative description of the available faked audio datasets. The article introduces types of AD attacks and then outlines and analyzes the detection methods and datasets for imitation- and synthetic-based Deepfakes. To the best of the authors’ knowledge, this is the first review targeting imitated and synthetically generated audio detection methods. The similarities and differences of AD detection methods are summarized by providing a quantitative comparison that finds that the method type affects the performance more than the audio features themselves, in which a substantial tradeoff between the accuracy and scalability exists. Moreover, at the end of this article, the potential research directions and challenges of Deepfake detection methods are discussed to discover that, even though AD detection is an active area of research, further research is still needed to address the existing gaps. This article can be a starting point for researchers to understand the current state of the AD literature and investigate more robust detection models that can detect fakeness even if the target audio contains accented voices or real-world noises.
A Counterfactual Framework Based on the Machine Learning Method and Its Application to Measure the Impact of COVID-19 Local Outbreaks on the Chinese Aviation Market
Authors: Zhang Linfeng , Tang Hongwu , Bian Lei
Published: May 2022

COVID-19 affects aviation around the world. China’s civil aviation almost recovered to its pre-epidemic levels in the domestic market, but there are still local outbreaks that affect air traffic. This paper proposes measuring the impact of local outbreaks of COVID-19 by the machine learning method and the synthetic control method as a counterfactual control group to measure such an impact. In this study, we use the LightGBM algorithm to construct a counterfactual control group and transform the prediction problem from time series to the fitting problem at the spatial level. We find that machine learning methods can measure such an impact more accurately. We take local outbreaks in Beijing and Dalian as examples, and our measure of their impacts shows that the impact of an outbreak on intercity air traffic can be divided into lag, decline, stable, and recovery periods, and will last for a long period (more than 40 days) unless there are external stimuli, such as legal holidays. The outbreaks reduced the number of passengers in the cities by 90%. Finally, we show the impact on the air traffic network, and find that when a local outbreak happens in a big city, tourist cities or small stations will be greatly affected.
A Civil Aircraft Cockpit Layout Evaluation Method Based on Layout Design Principles
Authors: Cao Kang , Zhang Yongjie , Jiang Yuefan , Zeng Yongqi , Cui Bo , Dong Wenjun
Published: May 2022

As technology continues to leap forward and innovations advance, the systems of civil aircraft are becoming increasingly sophisticated and complex. Accordingly, there is a rising amount of information to be processed by pilots in the cockpit, increasing their cognitive burden, which significantly threatens the safety of flight. Thus, designers have formulated cockpit layout principles relating to importance, frequency of use, functional grouping, and operation sequence on the basis of ergonomics, which can effectively reduce the cognitive burden for pilots. The degree to which the cockpit layout of a model conforms to the four design principles can indicate its ergonomic design level. In accordance with the concepts of the above four cockpit layout principles, evaluation methods for determining their respective conformity to the four design principles were proposed in this paper. These methods use the operational sequence of cockpit system controls used in the normal flight mission of the actual aircraft type as the evaluation data source. Subsequently, the total evaluation results for cockpit layout were obtained using the weighted accumulation method. Lastly, the process for evaluating the cockpit layouts of civil aircraft was illustrated using the cockpits of the A320 series and B737NG series as examples. Based on the final evaluation results, the feasibility and effectiveness of the proposed evaluation method was verified.
A Calibration Method for Contact Parameters of Maize Kernels Based on the Discrete Element Method
Authors: Li Hongcheng , Zeng Rong , Niu Zhiyou , Zhang Junqi
Published: May 2022

Clarifying the maize kernel movement during the crushing process is critical for improving the design and optimization of the impact mill. Rather than through experiments, maize kernel movement can be quantitatively analyzed through the discrete element method (DEM), and this could contribute more to the study of the crushing mechanism and equipment optimization. However, having an accurate particle model and contact parameters are prerequisites to ensure the accuracy of the DEM simulation. In this study, we proposed a maize kernel model construction method for the Rocky DEM simulation and a calibration method to calibrate contact parameters. The three-axis size, volume, and shape information of real maize kernels were obtained by 3D scanning, and then the maize kernel model was constructed by the section method. The particle–low-carbon-plate (p–w) and particle–particle (p–p) restitution coefficients were calibrated by using the improved inclined surface drop method. In addition, the angle of repose (AoR) and discharging time were considered together to calibrate the dynamical friction coefficients of p–w and p–p through the funnel method. Additionally, the maize kernel model and calibrated parameter values were used in a DEM simulation of the inclined surface drop test and the funnel test. The maximum relative errors between the simulation values and the measured values of the inclined surface drop test and the funnel test were 4.38% and 6.98%, respectively, which further verified that the proposed maize kernel model construction and contact parameter calibration methods are feasible and accurate. The research method used in this study is a novel idea that can be applied for the construction of the particle model and calibration of the contact parameters of granular materials with complex geometric structures, as well as the maize kernel model, and shows that calibrated contact parameters can provide a reference for the maize kernel crushing simulation to optimize the impact mill.
Modernizing Medical Research to Benefit People and Animals
Authors: Hutchinson Isobel , Owen Carla , Bailey Jarrod
Published: May 2022

In the context of widespread public and political concern around the use of animals in research, we sought to examine the scientific, ethical and economic arguments around the replacement of animals with New Approach Methodologies (NAMs) and to situate this within a regulatory context. We also analyzed the extent to which animal replacement aligns with British public and policymakers’ priorities and explored global progress towards this outcome. The global context is especially relevant given the international nature of regulatory guidance on the safety testing of new medicines. We used a range of evidence to analyze this area, including scientific papers; expert economic analysis; public opinion polls and the Hansard of the UK Parliament. We found evidence indicating that replacing animals with NAMs would benefit animal welfare, public health and the economy. The majority of the British public is in favor of efforts to replace animals and focusing on this area would help to support the British Government’s current policy priorities. We believe that this evidence underlines the need for strong action from policymakers to accelerate the transition from animal experiments to NAMs. The specific measure we suggest is to introduce a new ministerial position to coordinate and accelerate the replacement of animals with NAMs.
Effect of Fish Stock Density on Hormone Genes Expression from Brain and Gastrointestinal Tract of Salmo salar
Authors: Álvarez Claudio A. , Santana Paula A. , Cárcamo Claudia B. , Cárdenas Constanza , Morales-Lange Byron , Ramírez Felipe , Valenzuela Cristian , Boltaña Sebastián , Alcaíno Javier , Guzmán Fanny , Mercado Luis
Published: May 2022

A variety of long-term stress conditions may exist in fish cultivation, some of which are so severe that fish can no longer reestablish homeostasis. In teleost fish, the brain and gastrointestinal tract integrate signals that include the perception of stress factors regulating physiological responses, such as social stress by fish population density, where peripheral and central signals, such as peptide hormones, are the main regulators. Therefore, we proposed in this study to analyze the effect of different stock densities (SD) in the gene expression of brain neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP), together with the gastrointestinal peptide hormones leptin (Lep), vasointestinal peptide (VIP), and protachykinin-1 (Prk-1) in Salmo salar post-smolt. The coding sequence of S. salar VIP and Prk-1 precursors were firstly cloned and characterized. Then, the mRNA expression of these genes, together with the NPY, Lep, and CGRP genes, were evaluated in post-smolts kept at 11 Kg/m3, 20 Kg/m3, and 40 Kg/m3. At 14 days of culture, the brain CGRP and liver leptin mRNA levels increased three and tenfold in the post-smolt salmons kept at the highest SD, respectively. The high levels of leptin were kept during all the fish culture experiments. In addition, the highest expression of intestine VIP mRNA was obtained on Day 21 in the group of 40 Kg/m3 returning to baseline on Day 40. In terms of stress biochemical parameters, cortisol levels were increased in the 20 Kg/m3 and 40 Kg/m3 groups on Day 40 and were the highest in the 20 Kg/m3 group on Day 14. This study provides new insight into the gastrointestinal signals that could be affected by chronic stress induced by high stock density in fish farming. Thus, the expression of these peptide hormones could be used as molecular markers to improve production practices in fish aquaculture.
Insularity and Aridity as Drivers of Mandibular Disparity in Thylamys elegans (Waterhouse, 1839) from Populations of the Atacama Desert, Chile
Authors: Arriagada José I. , Benítez Hugo A. , Toro Frederick , Suazo Manuel J. , Abarca Paulette , Canto Jhoann , Vilina Yerko A. , Cruz-Jofré Franco
Published: May 2022

Island ecosystems differ in several elements from mainland ecosystems and may induce variations related to natural selection and patterns of adaptation in most aspects of the biology of an organism. Thylamys elegans (Waterhouse, 1839) is a marsupial endemic to Chile, distributed from Loa River to Concepción. Historically, three subspecies have been described: Thylamys elegans elegans, Thylamys elegans coquimbensis and Thylamys elegans soricinus. For this research, two morphometric approaches and a biomechanical model were used to compare the mandible shapes and biomechanics between two Chilean mouse opossum populations belonging to different subspecies: one from the coastal desert of Chile (T. e. coquimbensis) and the other from the central inland region (T. e. elegans). Additionally, mandibles of insular populations found in the Reserva Nacional Pinguino de Humboldt (RNPH)), from which the subspecies association is unknown, were also included. The results showed that insular populations have differences in mandibular shapes, sizes and biomechanical characteristics compared to continental populations, which may be related to environmental variables like aridity and vegetation cover, prey type, insularity effects and/or the founder effect on micromammals, apart from vicariance hypotheses and other selective pressures.
Screening of Natural Molecules as Adjuvants to Topical Antibiotics to Treat Staphylococcus aureus from Diabetic Foot Ulcer Infections
Authors: Oliveira Diana , Borges Anabela , Saavedra Maria J. , Borges Fernanda , Simões Manuel
Published: May 2022

Diabetic foot ulcers (DFUs) are a common result of a complex secondary complication of diabetes mellitus. More than half of DFUs become infected due to frequent colonization with Staphylococcus aureus. The use of topical antibiotics is proposed, especially in combination with natural adjuvants, to minimize the negative impacts caused by generalized use of systemic antibiotics. In this study, 13 different phytochemicals—namely chalcone, juglone, cinnamic acid, trigonelline, Furvina—and four nitrovinylfuran derivatives—guaiazulene, α-bisabolol, farnesol and nerolidol—were selected to be tested as antibiotic enhancers. After minimum inhibitory and bactericidal concentration (MIC and MBC) determination of each molecule against different strains of S. aureus, including clinical isolates from diabetic foot wounds (CECT 976, Xu212, SA 1199B, RN4220, MJMC102, MJMC109, MJMC110 and MJMC111), their potentiation effects on the antibiotics fusidic acid, mupirocin, gentamicin, oxacillin and methicillin were evaluated through the disc diffusion method. Farnesol at sub-MIC was able to restore the activity of methicillin and oxacillin on the MJMC102 and MJMC111 strains, as well as two MRSA clinical isolates, and potentiated the effect of the remaining antibiotics. The results obtained demonstrate the great potential for the topical application of phytochemicals and derivatives as antibiotic resistance modifier agents to combat multidrug resistance in bacterial wound infections.
Full-Parallax Multiview Generation with High-Speed Wide-Angle Dual-Axis Scanning Optics
Authors: Heo Daerak , Lim Sungjin , Lee Gunhee , Choi Geunseop , Hahn Joonku
Published: May 2022

Three-dimensional displays are receiving considerable attention owing to their ability to deliver realistic content. Particularly, a multiview display with temporal multiplexing offers advantages in terms of fewer restrictions for optical alignment and flexibility in forming view density. However, most of studies realize horizontal parallax-only multiview display. In a horizontal parallax-only multiview display the content is distorted in the vertical direction as the observer changes the viewing distance. It is helpful to understand this phenomenon using the Wigner distribution function (WDF). In this study, we divided the viewing zone (VZ) into the sub-viewing zone and integrated viewing zone according to the number of views of the observer. Specifically, the changes in the contents are experimentally evaluated at different viewing distances to validate our expectation. For the experiment, we implemented a full-parallax multiview display with spherical symmetry and designed a high-speed wide-angle dual-axis scanner. This scanner comprises two single-axis scanners connected by high numerical-aperture scanning optics. The proposed system and WDF analysis of VZ will be helpful to evaluate the characteristics of the multiview system.
Two-Stage Deep Learning Method for Breast Cancer Detection Using High-Resolution Mammogram Images
Authors: Ibrokhimov Bunyodbek , Kang Justin-Youngwook
Published: May 2022

Breast cancer screening and detection using high-resolution mammographic images have always been a difficult task in computer vision due to the presence of very small yet clinically significant abnormal growths in breast masses. The size difference between such masses and the overall mammogram image as well as difficulty in distinguishing intra-class features of the Breast Imaging Reporting and Database System (BI-RADS) categories creates challenges for accurate diagnosis. To obtain near-optimal results, object detection models should be improved by directly focusing on breast cancer detection. In this work, we propose a new two-stage deep learning method. In the first stage, the breast area is extracted from the mammogram and small square patches are generated to narrow down the region of interest (RoI). In the second stage, breast masses are detected and classified into BI-RADS categories. To improve the classification accuracy for intra-classes, we design an effective tumor classification model and combine its results with the detection model’s classification scores. Experiments conducted on the newly collected high-resolution mammography dataset demonstrate our two-stage method outperforms the original Faster R-CNN model by improving mean average precision (mAP) from 0.85 to 0.94. In addition, comparisons with existing works on a popular INbreast dataset validate the performance of our two-stage model.
Tongue Pressure Declines Early on in Patients with Malocclusion
Authors: Kuwajima Yukinori , Kim Grace , Ishida Yoshiki , Matsumoto Shikino , Ogawa Kaho , Shimpo Reiko , Shimpo Joichi , Nagasaki Hiroshi , Nagai Shigemi , Chen Chia-Yu
Published: May 2022

(1) Background: The tongue plays a key role in the stomatognathic system in carrying out oral functions. The aim of this study was to identify the association between tongue pressure and orthodontic parameters. (2) Methods: This study is a cross-sectional multicentered cohort study with IRB approval. During routine orthodontic initial examinations, the following data were recorded: age, sex, angle classification, overjet (OJ), overbite (OB), arch sizes, tongue width, and maximum tongue pressure (MTP). The association between MTP and orthodontic parameters was analyzed using Pearson’s correlation analysis and the Student’s t-test. (3) Results: There is a positive correlation between MTP and age between ages 10 and 20 (R = 0.47, p < 0.01). There is a negative correlation with MTP and age between 20 and 40 (R = −0.30, p < 0.05). There are negative correlations between MTP and OJ (R = −0.278, p < 0.01)) and OB (R = −0.374, p < 0.01). While there is no statistical significance between MTP and tongue width, there is a statistically significant difference between age and tongue width (R = 0.22482, p < 0.05). There is no statistical significance between MTP and sex, angle classification, arch length, intercanine width, and intermolar width. (4) Conclusion: An earlier decline in MTP is observed with patients with malocclusion. This implies that patients with malocclusion should seek early treatment for the malocclusion.
Maxillary Skeletal Expansion with Monocortical and Bicortical Miniscrew Anchorage: A 3D Finite Element Study
Authors: Liu Pao-Hsin , Chen Yu-Feng , Pan Chin-Yun , Sheen Ming-Hsuan , Chen Bang-Sia , Chang Hong-Po
Published: May 2022

The aim of the present study is to use a 3D finite element analysis to investigate and compare the transverse displacement and stress distribution between stainless steel miniscrews and titanium alloy miniscrews used for monocortical and bicortical anchorage during miniscrew-assisted rapid maxillary expansions. Skull models were constructed to depict expansion after and before midpalatal suture opening at varying miniscrew insertion depths in four clinical scenarios: monocortical, monocortical deepening, bicortical, and bicortical deepening. Finite element analyses of miniscrew properties, including transverse displacement and von Mises stress distribution, were performed for each clinical scenario. Peri-implant stress was lesser in both bicortical anchorage models compared to both monocortical models. Transverse displacement in the coronal and axial planes was also greater and more parallel in both bicortical models compared to both monocortical models. Transverse displacement and peri-implant stress did not significantly differ between monocortical and monocortical deepening models or between bicortical and bicortical deepening models. From a biomechanical perspective, the bicortical deepening miniscrew anchorage is preferable to monocortical and monocortical deepening anchorage, because bicortical anchorage induces less stress on the peri-implant bone. Consequently, bicortical deepening anchorage should be considered the preferred option in challenging clinical scenarios in which strong anchorage is required for maxillary skeletal expansion.
Microglia Depletion from Primary Glial Cultures Enables to Accurately Address the Immune Response of Astrocytes
Authors: Van Zeller Mariana , Sebastião Ana M. , Valente Cláudia A.
Published: May 2022

Astrocytes are the most abundant cells in the CNS parenchyma and play an essential role in several brain functions, such as the fine-tuning of synaptic transmission, glutamate uptake and the modulation of immune responses, among others. Much of the knowledge on the biology of astrocytes has come from the study of rodent primary astrocytic cultures. Usually, the culture is a mixed population of astrocytes and a small proportion of microglia. However, it is critical to have a pure culture of astrocytes if one wants to address their inflammatory response. If present, microglia sense the stimulus, rapidly proliferate and react to it, making it unfeasible to assess the individual responsiveness of astrocytes. Microglia have been efficiently eliminated in vivo through PLX-3397, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor. In this work, the effectiveness of PLX-3397 in eradicating microglia from primary mixed glial cultures was evaluated. We tested three concentrations of PLX-3397—0.2 μM, 1 μM and 5 μM—and addressed its impact on the culture yield and viability of astrocytes. PLX-3397 is highly efficient in eliminating microglia without affecting the viability or response of cultured astrocytes. Thus, these highly enriched monolayers of astrocytes allow for the more accurate study of their immune response in disease conditions.
Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function: Review on Mathematical Modelling Approaches
Authors: Pacini Giovanni , Ahrén Bo , Göbl Christian , Tura Andrea
Published: May 2022

Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.
Characterization of Mast Cells from Healthy and Varicose Human Saphenous Vein
Authors: Callesen Katrine T. , Mogren Sofia , Berlin Frida , Andersson Cecilia , Schmidt Susanne , Klitfod Lotte , Esteban Vanesa , Poulsen Lars K. , Jensen Bettina M.
Published: May 2022

Mast cells (MCs) are distributed in tissues throughout the body and are highly involved in many physiological and pathophysiological processes. The potential and involvement of different MC phenotypes are still not well understood. MCs are present in blood vessel walls, but their specific phenotypic features are unknown. We aimed at characterizing MCs from human saphenous veins for localization, mediator content, and receptor expression. This was done in MCs from both healthy and varicose human saphenous veins (hSV and vSV, respectively). For both vSV and hSV, we found that vein MCs are mainly present in the tunica adventitia (99% MCs in adventitia) and that the population consists of both MCT and MCTC phenotypes (vSV: 55% MCT, hSV: 64% MCT). The vein MCs contained high levels of histamine (vSV: 27 pg/MC, hSV: 55 pg/MC) and tryptase (vSV: 98 pg/MC, hSV: 111 pg/MC), indicating a strong potential for regulatory effects on blood vessels. The receptor expression of FcεRI, MRGPRX2, PTAFR, C3aR, and C5aR was found, even though the percentage of positive cells differed between vSV and hSV MCs. We conclude that vein MCs from the blood vessel wall have a high potential to affect the tissue around them.
The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor
Authors: Herzig Volker , Chen Yong-Cyuan , Chin Yanni K.-Y. , Dekan Zoltan , Chang Yu-Wang , Yu Hui-Ming , Alewood Paul F. , Chen Chien-Chang , King Glenn F.
Published: May 2022

Inhibition of T-type calcium channels (CaV3) prevents development of diseases related to cardiovascular and nerve systems. Further, knockout animal studies have revealed that some diseases are mediated by specific subtypes of CaV3. However, subtype-specific CaV3 inhibitors for therapeutic purposes or for studying the physiological roles of CaV3 subtypes are missing. To bridge this gap, we employed our spider venom library and uncovered that Avicularia spec. (“Amazonas Purple”, Peru) tarantula venom inhibited specific T-type CaV channel subtypes. By using chromatographic and mass-spectrometric techniques, we isolated and sequenced the active toxin ω-Avsp1a, a C-terminally amidated 36 residue peptide with a molecular weight of 4224.91 Da, which comprised the major peak in the venom. Both native (4.1 μM) and synthetic ω-Avsp1a (10 μM) inhibited 90% of CaV3.1 and CaV3.3, but only 25% of CaV3.2 currents. In order to investigate the toxin binding site, we generated a range of chimeric channels from the less sensitive CaV3.2 and more sensitive CaV3.3. Our results suggest that domain-1 of CaV3.3 is important for the inhibitory effect of ω-Avsp1a on T-type calcium channels. Further studies revealed that a leucine of T-type calcium channels is crucial for the inhibitory effect of ω-Avsp1a.
Rational Discovery of Antiviral Whey Protein-Derived Small Peptides Targeting the SARS-CoV-2 Main Protease
Authors: Gambacorta Nicola , Caputo Leonardo , Quintieri Laura , Monaci Linda , Ciriaco Fulvio , Nicolotti Orazio
Published: May 2022

In the present work, and for the first time, three whey protein-derived peptides (IAEK, IPAVF, MHI), endowed with ACE inhibitory activity, were examined for their antiviral activity against the SARS-CoV-2 3C-like protease (3CLpro) and Human Rhinovirus 3C protease (3Cpro) by employing molecular docking. Computational studies showed reliable binding poses within 3CLpro for the three investigated small peptides, considering docking scores as well as the binding free energy values. Validation by in vitro experiments confirmed these results. In particular, IPAVF exhibited the highest inhibitory activity by returning an IC50 equal to 1.21 μM; it was followed by IAEK, which registered an IC50 of 154.40 μM, whereas MHI was less active with an IC50 equal to 2700.62 μM. On the other hand, none of the assayed peptides registered inhibitory activity against 3Cpro. Based on these results, the herein presented small peptides are introduced as promising molecules to be exploited in the development of “target-specific antiviral” agents against SARS-CoV-2.
CD123 and More: How to Target the Cell Surface of Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Bôle-Richard Elodie , Pemmaraju Naveen , Caël Blandine , Daguindau Etienne , Lane Andrew A.
Published: May 2022

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia derived from plasmacytoid dendritic cells (pDCs). It is associated with a remarkably poor prognosis and unmet need for better therapies. Recently, the first-in-class CD123-targeting therapy, tagraxofusp, was approved for treatment of BPDCN. Other CD123-targeting strategies are in development, including bispecific antibodies and combination approaches with tagraxofusp and other novel agents. In other blood cancers, adoptive T-cell therapy using chimeric antigen receptor (CAR)-modified T cells represents a promising new avenue in immunotherapy, showing durable remissions in some relapsed hematologic malignancies. Here, we report on novel and innovative therapies in development to target surface molecules in BPDCN currently in clinical trials or in preclinical stages. We also discuss new cell surface targets that may have implications for future BPDCN treatment.
The Beneficial Role of Physical Exercise on Anthracyclines Induced Cardiotoxicity in Breast Cancer Patients
Authors: Tranchita Eliana , Murri Arianna , Grazioli Elisa , Cerulli Claudia , Emerenziani Gian Pietro , Ceci Roberta , Caporossi Daniela , Dimauro Ivan , Parisi Attilio
Published: May 2022

The increase in breast cancer (BC) survival has determined a growing survivor population that seems to develop several comorbidities and, specifically, treatment-induced cardiovascular disease (CVD), especially those patients treated with anthracyclines. Indeed, it is known that these compounds act through the induction of supraphysiological production of reactive oxygen species (ROS), which appear to be central mediators of numerous direct and indirect cardiac adverse consequences. Evidence suggests that physical exercise (PE) practised before, during or after BC treatments could represent a viable non-pharmacological strategy as it increases heart tolerance against many cardiotoxic agents, and therefore improves several functional, subclinical, and clinical parameters. At molecular level, the cardioprotective effects are mainly associated with an exercise-induced increase of stress response proteins (HSP60 and HSP70) and antioxidant (SOD activity, GSH), as well as a decrease in lipid peroxidation, and pro-apoptotic proteins such as Bax, Bax-to-Bcl-2 ratio. Moreover, this protection can potentially be explained by a preservation of myosin heavy chain (MHC) isoform distribution. Despite this knowledge, it is not clear which type of exercise should be suggested in BC patient undergoing anthracycline treatment. This highlights the lack of special guidelines on how affected patients should be managed more efficiently. This review offers a general framework for the role of anthracyclines in the physio-pathological mechanisms of cardiotoxicity and the potential protective role of PE. Finally, potential exercise-based strategies are discussed on the basis of scientific findings.
Denosumab in Giant Cell Tumor of Bone: Multidisciplinary Medical Management Based on Pathophysiological Mechanisms and Real-World Evidence
Authors: Borkowska Aneta Maria , Szumera-Ciećkiewicz Anna , Szostakowski Bartłomiej , Pieńkowski Andrzej , Rutkowski Piotr Lukasz
Published: May 2022

(1) Despite the benign nature of the giant cell tumor of bone (GCTB), it shows a local recurrence rate of up to 50% and a chance of malignant transformation. The widely accepted local therapy in extremity GCTB is surgery, in the form of extended intralesional curettage with adequate disease clearance and retention of the limb, wherever possible. Denosumab, a human monoclonal antibody directed against the RANKL and associated inhibition of the RANKL pathway, is a relevant therapy option for advanced GCTB, to benefit tumor response and surgical down-staging. (2) The literature review of patients with GCTB treated with denosumab is performed via PubMed, using suitable keywords from January 2009 to January 2021. (3) Current indications for denosumab use are not definitively clear and unambiguous. Most GCTB patients with localized disease can be successfully treated with surgical curettage, and the role of denosumab in preoperative therapy in this patient population remains unclear. (4) However, patients with primary unresectable lesions or metastases may experience long-term clinical and radiological remission and pain control with denosumab treatment, and in this clinical situation, denosumab is currently the treatment of choice.
Hypoxia as a Modulator of Inflammation and Immune Response in Cancer
Authors: Castillo-Rodríguez Rosa A. , Trejo-Solís Cristina , Cabrera-Cano Alfredo , Gómez-Manzo Saúl , Dávila-Borja Víctor Manuel
Published: May 2022

A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the tumoral mass, defined as tumoral hypoxia. Moreover, hypoxia not only influences the tumoral cells but also the surrounding cells, including those related to the inflammatory processes. In this review, we analyze the participation of HIF, NF-κB, and STAT signaling pathways as the main components that interconnect hypoxia and immune response and how they modulate tumoral growth. In addition, we closely examine the participation of the immune cells and how they are affected by hypoxia, the effects of the progression of cancer, and some innovative applications that take advantage of this knowledge, to suggest potential therapies. Therefore, we contribute to the understanding of the complexity of cancer to propose innovative therapeutic strategies in the future.
Blood Eosinophils Are Associated with Efficacy of Targeted Therapy in Patients with Advanced Melanoma
Authors: Wendlinger Simone , Wohlfarth Jonas , Kreft Sophia , Siedel Claudia , Kilian Teresa , Dischinger Ulrich , Heppt Markus V. , Wistuba-Hamprecht Kilian , Meier Friedegund , Goebeler Matthias , Schadendorf Dirk , Gesierich Anja , Kosnopfel Corinna , Schilling Bastian
Published: May 2022

Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.
Novel Enzymatic Method for Imine Synthesis via the Oxidation of Primary Amines Using D-Amino Acid Oxidase from Porcine Kidney
Authors: Kawahara Nobuhiro , Palasin Kunwadee , Asano Yasuhisa
Published: May 2022

During studies on the oxidative cyanation reaction catalyzed by a variant of D-amino acid oxidase from porcine kidney (pkDAO) (Y228L/R283G), an unexpected formation of 1-phenyl-N-(1-phenylethylidene)ethanamine (PPEA) was detected. The optimal reaction conditions for the synthesis of PPEA and the reaction mechanism were investigated using the pkDAO variant. The highest PPEA synthesis was obtained in the reaction with 150 mM (R)-MBA at pH 9.0 and at 20 °C. Since PPEA synthesis proceeded by trapping the intermediate 1-phenylethanimine (1-PEI) by 15N-labeled n-hexylamine, which is not a substrate for the pKDAO variant, it was deduced that PPEA would be synthesized by a nucleophilic substitution of 1-PEI by another molecule of (R)-MBA. PPEA was further identified by its conversion to bis(1-phenylethyl)amine (BPEA) through reduction with NaBH4. Thus, a new enzymatic method of imine synthesis by oxidation of primary amine by the variant pkDAO was achieved for the first time.
Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis
Authors: Chen I-Chen , Liu Yi-Ching , Wu Yen-Hsien , Lo Shih-Hsing , Dai Zen-Kong , Hsu Jong-Hau , Tseng Yu-Hsin
Published: May 2022

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, and it has a worse prognosis than non-small cell lung cancer. The pathomechanism of IPF is not fully understood, but it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts. These activated myofibroblasts express α smooth muscle actin and release extracellular matrix to promote matrix deposition and tissue remodeling. Under physiological conditions, the remodeling process stops once wound healing is complete. However, in the lungs of IPF patients, myofibroblasts re-main active and deposit excess extracellular matrix. This leads to the destruction of alveolar tissue, the loss of lung elastic recoil, and a rapid decrease in lung function. Some evidence has indicated that proteasomal inhibition combats fibrosis by inhibiting the expressions of extracellular matrix proteins and metalloproteinases. However, the mechanisms by which proteasome inhibitors may protect against fibrosis are not known. This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasome inhibitors have the potential to become new drugs for the treatment of pulmonary fibrosis.
Algebraic Zero Error Training Method for Neural Networks Achieving Least Upper Bounds on Neurons and Layers
Authors: Kacur Juraj
Published: May 2022

In the domain of artificial neural networks, it is important to know what their representation, classification and generalization capabilities are. There is also a need for time and resource-efficient training algorithms. Here, a new zero-error training method is derived for digital computers and single hidden layer networks. This method is the least upper bound on the number of hidden neurons as well. The bound states that if there are N input vectors expressed as rational numbers, a network having N − 1 neurons in the hidden layer and M neurons at the output represents a bounded function F: RD→RM for all input vectors. Such a network has massively shared weights calculated by 1 + M regular systems of linear equations. Compared to similar approaches, this new method achieves a theoretical least upper bound, is fast, robust, adapted to floating-point data, and uses few free parameters. This is documented by theoretical analyses and comparative tests. In theory, this method provides a new constructional proof of the least upper bound on the number of hidden neurons, extends the classes of supported activation functions, and relaxes conditions for mapping functions. Practically, it is a non-iterative zero-error training algorithm providing a minimum number of neurons and layers.