bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement and Verification of One-Dimensional Numerical Algorithm for Reservoir Water Temperature at the Front of Dams
Authors: Zheng Xuerui , Shen Zhenzhong , Wang Zhenhong , Qiang Sheng , Yuan Min
Published: June 2022

The deep-water temperature of large reservoirs is low, thus easily leads to the appearance and expansion of cracks on the upstream faces of concrete dams. Therefore, in the design phase of a dam, accurately predicting the water temperature distribution at the front of the dam during the operation period of the reservoir takes on a critical significance in the dam simulation analysis of temperature control and crack prevention design. The vertical one-dimensional numerical algorithm of reservoir water temperature was optimized in accordance with the heat transfer equation and considering certain factors (e.g., water temperature transfer, inflow distribution, slag at the bottom of the reservoir, and solar radiation) to solve the above problem. The Nash–Sutcliffe efficiency coefficient (NSE) was adopted to analyze the simulation error qualitatively and quantitatively, and to verify the applicability of the algorithm. The results validated with temperature data measured in four reservoirs illustrate that the proposed algorithm exhibits a higher prediction accuracy than the empirical equation method for water temperature at the front of dams at different scales under different operation modes. The mean deviations of the proposed algorithm are all below 1 °C, and the Nash–Sutcliffe efficiency coefficients (NSE) are all above 0.85. Moreover, compared with the three-dimensional numerical algorithm, the proposed algorithm not only requires a smaller amount of data, but also is simpler to apply and has a higher efficiency. The twelve-month water temperature calculation for a large reservoir takes less than 1 min. This study further reveals that the slag at the bottom of the reservoir is capable of significantly rising the temperature at the dam heel by 5–6 °C. The program compiled by the proposed algorithm can be seamlessly embedded in the simulation program for concrete dam temperature control; thus, the reliability of the simulation of the temperature can be enhanced for temperature field and stress field on the upstream surface of the dam without affecting the total calculation efficiency.
An Efficient AdaBoost Algorithm with the Multiple Thresholds Classification
Authors: Ding Yi , Zhu Hongyang , Chen Ruyun , Li Ronghui
Published: June 2022

Adaptive boost (AdaBoost) is a prominent example of an ensemble learning algorithm that combines weak classifiers into strong classifiers through weighted majority voting rules. AdaBoost’s weak classifier, with threshold classification, tries to find the best threshold in one of the data dimensions, dividing the data into two categories-1 and 1. However, in some cases, this Weak Learning algorithm is not accurate enough, showing poor generalization performance and a tendency to over-fit. To solve these challenges, we first propose a new Weak Learning algorithm that classifies examples based on multiple thresholds, rather than only one, to improve its accuracy. Second, in this paper, we make changes to the weight allocation scheme of the Weak Learning algorithm based on the AdaBoost algorithm to use potential values of other dimensions in the classification process, while the theoretical identification is provided to show its generality. Finally, comparative experiments between the two algorithms on 18 datasets on UCI show that our improved AdaBoost algorithm has a better generalization effect in the test set during the training iteration.
Microalgae as Potential Sources of Bioactive Compounds for Functional Foods and Pharmaceuticals
Authors: Silva Mélanie , Kamberovic Farah , Uota Sisay Tesema , Kovan Ismael-Mohammed , Viegas Carla S. B. , Simes Dina C. , Gangadhar Katkam N. , Varela João , Barreira Luísa
Published: June 2022

Microalgae are an untapped source of bioactive compounds with various biotechnological applications. Several species are industrially produced and commercialized for the feed or cosmetic industries, however, other applications in the functional food and pharmaceutical markets can be foreseen. In this study, nine industrial/commercial species were evaluated for in vitro antioxidant, calcium-chelating, anti-tumoral, and anti-inflammatory activities. The most promising extracts were fractionated yielding several promising fractions namely, of Tetraselmis striata CTP4 with anti-inflammatory activity (99.0 ± 0.8% reduction in TNF-α production in LPS stimulated human macrophages at 50 µg/mL), of Phaeodactylum Tricornutum with cytotoxicity towards cancerous cell lines (IC50 = 22.3 ± 1.8 μg/mL and 27.5 ± 1.6 μg/mL for THP-1 and HepG2, respectively) and of Porphyridium sp. and Skeletonema sp. with good chelating activity for iron, copper and calcium (IC50 = 0.047, 0.272, 0.0663 mg/mL and IC50 = 0.055, 0.240, 0.0850 mg/mL, respectively). These fractions were chemically characterized by GC–MS after derivatization and in all, fatty acids at various degrees of unsaturation were the most abundant compounds. Some of the species under study proved to be potentially valuable sources of antioxidant, metal chelators, anti-tumoral and anti-inflammatory compounds with possible application in the functional food and pharmaceutical industries.
Extracting Searching as Learning Tasks Based on IBRT Approach
Authors: Li Pengfei , Zhang Bin , Zhang Yin
Published: June 2022

With the rapid development of the World Wide Web and information retrieval technology, learning supported by searching engines (such as making travel plans) has boomed over the past years. With the help of search engines, learners can easily retrieve and find large amounts of information on the web. Recent research in the searching as learning (SAL) area has associated web searching with learning. In SAL processes, web learners recursively plan tasks, formulate search queries, obtain information from web pages, and change knowledge structures, to gradually complete their learning goals. To improve the experiences of web learners, it is important to accurately present and extract tasks. Using learning styles and similarity metrics, we first proposed an IBRT model to implement structured representations of the SAL process for each learner. SAL tasks were then extracted from the structures of IBRT. In this study, a series of experiments were carried out against assignment datasets from the Northeastern University (China) UWP Programming Course. Comparison results show that the proposed method can significantly improve the performance of SAL task extraction.
Category Theory Framework for System Engineering and Safety Assessment Model Synchronization Methodologies
Authors: Vidalie Julien , Batteux Michel , Mhenni Faïda , Choley Jean-Yves
Published: June 2022

In recent decades, there has been a significant increase in systems’ complexity, leading to a rise in the need for more and more models. Models created with different intents are written using different formalisms and give diverse system representations. This work focuses on the system engineering domain and its models. It is crucial to assert a critical system’s compliance with its requirements. Thus, multiple models dedicated to these assertions are designed, such as safety or multi-physics models. As those models are independent of the architecture model, we need to provide means to assert and maintain consistency between them if we want the analyses to be relevant. The model synchronization methodologies give means to work on the consistency between the models through steps of abstraction to a common formalism, comparison, and concretization of the comparison results in the original models. This paper proposes a mathematical framework that allows for a formal definition of such a consistency relation and a mathematical description of the models. We use the context of category theory, as this is a mathematical theory providing great tools for taking into account different abstraction levels and composition of relations. Finally, we show how this mathematical framework can be applied to a specific synchronization methodology with a realistic study case.
Biomaterials for Ophthalmic Applications
Authors: Ferraz Maria Pia
Published: June 2022

Ophthalmology is the branch of medicine that deals with diseases of the eye, the organ responsible for vision, and its attachments. Biomaterials can be made with different types of materials and can replace or improve a function or an organ, specifically the eye in the case of ophthalmic biomaterials. Biomaterials are substances that interact with biological systems for a medical purpose, either as a therapeutic (treat, augment, repair, or replace a tissue function of the body) or a diagnostic agent, and have continued to improve over the years, leading to the creation of new biomaterials. With the arrival of new generations, biomaterials have succeeded in reducing complications and toxicity and improving biocompatibilities associated with older generations. With the aging population, eye problems are becoming more prevalent, and biomaterials have helped in recent years to improve or restore vision, improving the quality of life of many patients. This review focuses on the most clinically used ophthalmic biomaterials, including contact lenses, intraocular lenses, artificial tears, inlays and vitreous replacements. Tissue engineering is presented as a new tool that is able to be treat several ophthalmologic disorders.
Analysis of Gut Microbiome Structure Based on GMPR+Spectrum
Authors: Xiong Xin , Ren Yuyan , He Jianfeng
Published: June 2022

The gut microbiome is related to many major human diseases, and it is of great significance to study the structure of the gut microbiome under different conditions. Multivariate statistics or pattern recognition methods were often used to identify different structural patterns in gut microbiome data. However, these methods have some limitations. Minimal hepatic encephalopathy (MHE) datasets were taken as an example. Due to the physical lack or insufficient sampling of the gut microbiome in the sequencing process, the microbiome data contains many zeros. Therefore, the geometric mean of pairwise ratios (GMPR) was used to normalize gut microbiome data, then Spectrum was used to analyze the structure of the gut microbiome, and lastly, the structure of core microflora was compared with Network analysis. GMPR calculates the Intraclass correlation coefficient (ICC), whose reproducibility was significantly better than other normalization methods. In addition, running-time, Normalized Mutual Information (NMI), Davies-Boulding Index (DBI), and Calinski-Harabasz index (CH) of GMPR+Spectrum were far superior to other clustering algorithms such as M3C, iClusterPlus. GMPR+Spectrum can not only perform better but also effectively identify the structural differences of intestinal microbiota in different patients and excavate the unique critical bacteria such as Akkermansia, and Lactobacillus in MHE patients, which may provide a new reference for the study of the gut microbiome in disease.
Identification of Smoke from Straw Burning in Remote Sensing Images with the Improved YOLOv5s Algorithm
Authors: Liu Hua , Li Jian , Du Jia , Zhao Boyu , Hu Yating , Li Dongming , Yu Weilin
Published: June 2022

Controlling straw burning is important for ensuring the ambient air quality and for sustainable agriculture. Detecting burning straw is vital for managing and controlling straw burning. Existing methods for detecting straw combustion mainly look for combustion products, especially smoke. In this study, the improved You Only Look Once version 5 (YOLOv5s) algorithm was used to detect smoke in Sentinel-2 images captured by remote sensing. Although the original YOLOv5s model had a faster detection speed, its detection accuracy was poor. Thus, a convolutional block attention module was added to the original model. In addition, in order to speed up the convergence of the model, this study replaced the leaky Rectified Linear Unit (leaky ReLU) activation function with the Mish activation function. The accuracy of the improved model was approximately 4% higher for the same detection speed. The improved YOLOv5s had a higher detection accuracy and speed compared to common target detection algorithms, such as RetinaNet, mask Region-Based Convolutional Neural Network (R-CNN), Single-Shot Multibox Detector (SSD), and faster R-CNN. The improved YOLOv5s analyzed an image in 2 ms. In addition, mAP50 exceeded 94%, demonstrating that with this study’s improved method, smoke can be quickly and accurately identified. This work may serve as a reference for improving smoke detection, and for the effective management and control of straw burning.
The March 2012 Heat Wave in Northeast America as a Possible Effect of Strong Solar Activity and Unusual Space Plasma Interactions
Authors: Anagnostopoulos Georgios C. , Menesidou Sofia-Anna I. , Efthymiadis Dimitrios A.
Published: June 2022

In the past two decades, the world has experienced an unprecedented number of extreme weather events, some causing major human suffering and economic damage. The March 2012 heat wave is one of the most known and broadly discussed events in the Northeast United States (NE-USA). The present study examines in depth the possible influence of solar activity on the historic March 2012 heat wave based on a comparison of solar/space and meteorological data. Our research suggests that the historic March 2012 heat wave (M2012HW) and the March 1910 heat wave (M1910HW), which occurred a century earlier in NE-USA, were related to Sun-generated special space plasma structures triggering large magnetic storms. Furthermore, the largest (Dst = −222 nT) magnetic storm during solar cycle 24 in March 2015 (only three years later than the March 2012 events) occurred in relation to another heat wave (M2015HW) in NE-USA. Both these heat waves, M2012HW and M2015HW, resemble each other in many ways: they were characterized by extremely huge temperature increases ΔΤΜ = 30° and 32° (with maximum temperatures ΤΜ = 28° and 23°, respectively) during a positive North Atlantic Oscillation index, the high temperatures coincided with large-scale warm air streaming from southern latitudes, they were accompanied by superstorms caused by unexpected geoeffective interplanetary coronal mass ejections (ICMEs), and the ICME-related solar energetic particle (SEP) events were characterized by a proton spectrum extending to very high (>0.5 GeV) energies. We infer that (i) all three heat waves examined (M2012HW, M2015HW, M1910HW) were related with strong magnetic storms triggered by effective solar wind plasma structures, and (b) the heat wave in March 2012 and the related solar activity was not an accidental coincidence; that is, the M2012HW was most probably affected by solar activity. Future case and statistical studies are needed to further check the hypothesis put forward here, which might improve atmospheric models in helping people’s safety, health and life.
Relationships between Aerosol and Raindrop Size Distributions during Rainfall Period (Changma) in Jeju Island, Korea
Authors: Jung Woonseon , Sung Hyun Min , You Cheol-Hwan , Kim Hyeon-Joon , Suh Sung-Ho , Lee Dong-In , Chang Ki-Ho
Published: June 2022

To investigate the variation in aerosol particles removed by rainfall, we determined the relationship between aerosols and raindrops observed on Jeju Island, Korea, during a heavy rainfall period (Changma) from 1–15 July 2012. Various instruments, including an aerodynamic particle sizer, rain gauge, and disdrometer, were installed at the Gosan meteorological observation site on Jeju Island. During the Changma period, precipitation between 0.7 and 25.4 mm per day was recorded, and large variations in aerosol and raindrop size distributions were observed. Aerosol removal by precipitation was indicated, and its scavenging effect was confirmed from the results. Three major parameters (Brownian diffusion, interception, and impaction) described the collision efficiency based on aerosol and raindrop size distributions. The variations in the scavenging coefficient and below-cloud scavenging rate produced similar results for the accumulated rain amount. Therefore, these field observations explained the relationship between aerosol and raindrop size distributions.
Spatiotemporal Analysis of MODIS Aerosol Optical Depth Data in the Philippines from 2010 to 2020
Authors: Caido Nadine Grace , Ong Prane Mariel , Rempillo Ofelia , Galvez Maria Cecilia , Vallar Edgar
Published: June 2022

Satellite remote sensing for air quality assessment provides information over a large spatial coverage and time period that shows the trends and effects of anthropogenic activities. Using data collected from the Moderate Resolution Imaging Spectroradiometer (MODIS) Terra satellite from the years 2010 to 2020, the spatiotemporal variations to aerosol optical depth (AOD) in Koronadal City and Quezon City were studied. Validation showed a strong relationship between the MODIS AOD values and the Aerosol Robotic Network (AERONET) AOD values (R2 = 0.83) and a low root mean square error (RMSE) of 0.26. Annual variation in the AOD of the two study areas showed a peak AOD value in 2015 due to an immense biomass burning in Indonesia and a low AOD value in 2020 due to the COVID-19 lockdown. Koronadal City experienced a high AOD value during the fall season due to aerosols from biomass burning in Indonesia that were carried by the southwest monsoon. Quezon City experienced a high AOD value during spring from increased local sources, as well as long-range transport pollutants from East Asia that were carried by northeasterly winds. Overall, this study provides an understanding of the spatiotemporal variations in aerosols in the Philippines, which could be used in environmental management, air quality regulations, and health assessment studies. This shows the urgency of monitoring and mitigating poor air quality in the Philippines.
Air Quality Sensor Networks for Evidence-Based Policy Making: Best Practices for Actionable Insights
Authors: Hofman Jelle , Peters Jan , Stroobants Christophe , Elst Evelyne , Baeyens Bart , Van Laer Jo , Spruyt Maarten , Van Essche Wim , Delbare Elke , Roels Bart , Cochez Ann , Gillijns Evy , Van Poppel Martine
Published: June 2022

(1) Background: This work evaluated the usability of commercial “low-cost” air quality sensor systems to substantiate evidence-based policy making. (2) Methods: Two commercially available sensor systems (Airly, Kunak) were benchmarked at a regulatory air quality monitoring station (AQMS) and subsequently deployed in Kampenhout and Sint-Niklaas (Belgium) to address real-world policy concerns: (a) what is the pollution contribution from road traffic near a school and at a central city square and (b) do local traffic interventions result in quantifiable air quality impacts? (3) Results: The considered sensor systems performed well in terms of data capture, correlation and intra-sensor uncertainty. Their accuracy was improved via local re-calibration, up to data quality levels for indicative measurements as set in the Air Quality Directive (Uexp < 50% for PM and <25% for NO2). A methodological setup was proposed using local background and source locations, allowing for quantification of the (3.1) maximum potential impact of local policy interventions and (3.2) air quality impacts from different traffic interventions with local contribution reductions of up to 89% for NO2 and 60% for NO throughout the considered 3 month monitoring period; (4) Conclusions: Our results indicate that commercial air quality sensor systems are able to accurately quantify air quality impacts from (even short-lived) local traffic measures and contribute to evidence-based policy making under the condition of a proper methodological setup (background normalization) and data quality (recurrent calibration) procedure. The applied methodology and learnings were distilled in a blueprint for air quality sensor networks for replication actions in other cities.
Enhancing Prednisone-Based Arthritis Therapy with Targeted IL-27 Gene Delivery
Authors: Marin Adriana A. , Decker Richard E. , Kumar Shreya , Lamantia Zachary , Yokota Hiroki , Emrick Todd , Figueiredo Marxa L.
Published: June 2022

Rheumatoid arthritis (RA) is a chronic autoimmune disease which is characterized primarily by synovial hyperplasia and accumulation of several types of immune infiltrates that promote progressive destruction of the articular structure. Glucocorticoids are often prescribed to treat RA because of their strong anti-inflammatory and immunosuppressive effects. However, their application must be limited to the short-term due to a risk of adverse events. In the present study, we examined the potential combination of low-dose prednisone with gene delivery of an agent of promising and complementary effectiveness in RA, interleukin (IL)-27. IL-27 has been shown to have anti-inflammatory potential, while also acting as an effective bone-normalization agent in prior reports. The present report examined a version of IL-27 targeted at the C-terminus with a short ‘peptide L’ (pepL, LSLITRL) that binds the interleukin 6 receptor α (IL-6Rα) upregulated during inflammation. By focusing on this targeted form, IL-27pepL or 27pL, we examined whether the anti-inflammatory potential of prednisone (at a relatively low dose and short duration) could be further enhanced in the presence of 27pL as a therapy adjuvant. Our results indicate that 27pL represents a novel tool for use as an adjuvant with current therapeutics, such as prednisone, against inflammatory conditions.
Four New Pale-Spored Species of Xylaria (Xylariaceae, Xylariales) with a Key to Worldwide Species on Fallen Fruits and Seeds
Authors: Ma Haixia , Song Zikun , Pan Xiaoyan , Qu Zhi , Yang Zhanen , Li Yu , Zhu Anhong
Published: June 2022

Xylaria, a large and cosmopolitan genus of Ascomycota, plays an important ecological role in forest ecology as wood-decomposers, and serve as a source of bioactive secondary metabolites. The present work concerns a survey of Xylaria from Southwest China. Four new species of Xylaria with pale-colored ascospores associated with fallen fruits and seeds are described and illustrated based on morphological and phylogenetic evidences. The phylogeny inferred from a combined dataset of ITS-RPB2-β-tubulin sequences supports these four species as distinct species. The four new taxa, namely Xylariarogersii, X. schimicola, X. theaceicola, and X. wallichii, are compared and contrasted against morphologically similar species. A dichotomous identification key to all the accepted species of Xylaria associated with fallen fruits and seeds is given.
Application of Optical Fluorescence Spectroscopy for Studying Bee Abundance in Tropaeolum majus L. (Tropaeolaceae)
Authors: Fioratti Claudemir Antonio Garcia , Falcão Evaristo Alexandre , da Silva Rosicleia Matias , do Carmo Vieira Maria , Caires Anderson Rodrigues Lima , Mussury Rosilda Mara
Published: June 2022

Tropaeolum majus L. species produce flowers with all sorts of colors, from yellow to red. This work aimed to apply optical fluorescence spectroscopy to study bee abundance in T. majus, answering the following questions: (1) do corolla temperature and weather conditions affect the abundance of visiting bee species? (2) do flower color and corolla fluorescence affect the abundance of visiting bee species? (3) do red flowers attract more visiting bees? (4) is there a relationship between bee visits and flower compounds? The bee species Apis mellifera, Paratrigona lineata, and Trigona spinipes were the most observed in T. majus flowers. The latter was more active in the morning and preferred orange and yellow flowers. These colors also had higher temperatures and fluorescence emissions than did the red ones and those with yellow-red and orange-red nectar guides. Orange flowers emitted a broadband UV spectrum (between 475 and 800 nm). This range might be due to compounds such as hydroxycinnamic acid, flavonols, isoflavonoids, flavones, phenolic acid, and chlorophyll. Extracts from different T. majus corolla colors showed that flowers emit specific fluorescent signals, mainly related to bee color vision and learning, thus acting as a means of communication between bees and flowers. In this way, this information evidences the interaction between bees and T. majus flowers, allowing conservation actions for pollinators.
Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis
Authors: Rodriguez-Mogeda Carla , Rodríguez-Lorenzo Sabela , Attia Jiji , van Horssen Jack , Witte Maarten E. , de Vries Helga E.
Published: June 2022

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.
Exploring Silk Sericin for Diabetic Wounds: An In Situ-Forming Hydrogel to Protect against Oxidative Stress and Improve Tissue Healing and Regeneration
Authors: Baptista-Silva Sara , Bernardes Beatriz G. , Borges Sandra , Rodrigues Ilda , Fernandes Rui , Gomes-Guerreiro Susana , Pinto Marta Teixeira , Pintado Manuela , Soares Raquel , Costa Raquel , Oliveira Ana Leite
Published: June 2022

Chronic wounds are one of the most frequent complications that are associated with diabetes mellitus. The overproduction of reactive oxygen species (ROS) is a key factor in the delayed healing of a chronic wound. In the present work, we develop a novel in situ-forming silk sericin-based hydrogel (SSH) that is produced by a simple methodology using horseradish peroxidase (HRP) crosslinking as an advanced dressing for wound healing. The antioxidant and angiogenic effects were assessed in vitro and in vivo after in situ application using an excisional wound-healing model in a genetically-induced diabetic db/db mice and though the chick embryo choriollantoic membrane (CAM) assay, respectively. Wounds in diabetic db/db mice that were treated with SSH closed with reduced granulation tissue, decreased wound edge distance, and wound thickness, when compared to Tegaderm, a dressing that is commonly used in the clinic. The hydrogel also promoted a deposition of collagen fibers with smaller diameter which may have had a boost effect in re-epithelialization. SSH treatment slightly induced two important endogenous antioxidant defenses, superoxide dismutase and catalase. A CAM assay made it possible to observe that SSH led to an increase in the number of newly formed vessels without inducing an inflammatory reaction. The present hydrogel may result in a multi-purpose technology with angiogenic, antioxidant, and anti-inflammatory properties, while advancing efficient and organized tissue regeneration.
TRPV6 Regulation by Cis-22a and Cholesterol
Authors: Humer Christina , Lindinger Sonja , Carrel Aline L. , Romanin Christoph , Höglinger Carmen
Published: June 2022

The highly calcium-selective transient receptor potential vanilloid-type channel TRPV6 is important for epithelial Ca2+ transport. Proper regulation of the inherently constitutively active TRPV6 channels is intricate in preserving Ca2+ homeostasis, whereby structural and functional data suggest that lipids hold an essential role. Altered expression levels or specific TRPV6 mutations may lead to diseases, hence, TRPV6 represents an interesting target for pharmacological modulation. Recent cryo-EM data identified that the specific TRPV6 blocker cis-22a binds, apart from the pore, to a site within the tetrameric channel that largely matches a lipid binding pocket, LBS-2. Therein, cis-22a may replace a lipid such as cholesterol that is bound in the open state. Based on site-directed mutagenesis and functional recordings, we identified and characterized a series of residues within LBS-2 that are essential for TRPV6 inhibition by cis-22a. Additionally, we investigated the modulatory potential of diverse cholesterol depletion efforts on TRPV6 activity. While LBS-2 mutants exhibited altered maximum currents, slow Ca2+-dependent inactivation (SCDI) as well as less inhibition by cis-22a, TRPV6 activity was resistant to cholesterol depletion. Hence, lipids other than cholesterol may predominate TRPV6 regulation when the channel is expressed in HEK293 cells.
Editorial on the Special Issue: “Multidrug Combinations”
Authors: Vale Nuno
Published: June 2022

Biological organisms are composed of complex subsystems that interact dynamically at different levels, with functions that are complemented to avoid system malfunctions [...]
A Potential Interplay between HDLs and Adiponectin in Promoting Endothelial Dysfunction in Obesity
Authors: Zocchi Monica , Della Porta Matteo , Lombardoni Federico , Scrimieri Roberta , Zuccotti Gian Vincenzo , Maier Jeanette A. , Cazzola Roberta
Published: June 2022

Obesity is an epidemic public health problem that has progressively worsened in recent decades and is associated with low-grade chronic inflammation (LGCI) in metabolic tissues and an increased risk of several diseases. In particular, LGCI alters metabolism and increases cardiovascular risk by impairing endothelial function and altering the functions of adiponectin and high-density lipoproteins (HDLs). Adiponectin is an adipokine involved in regulating energy metabolism and body composition. Serum adiponectin levels are reduced in obese individuals and negatively correlate with chronic sub-clinical inflammatory markers. HDLs are a heterogeneous and complex class of lipoproteins that can be dysfunctional in obesity. Adiponectin and HDLs are strictly interdependent, and the maintenance of their interplay is essential for vascular function. Since such a complex network of interactions is still overlooked in clinical settings, this review aims to highlight the mechanisms involved in the impairment of the HDLs/adiponectin axis in obese patients to predict the risk of cardiovascular diseases and activate preventive countermeasures. Here, we provide a narrative review of the role of LGCI in altering HDLs, adiponectin and endothelial functions in obesity to encourage new studies about their synergic effects on cardiovascular health and disease.
Olfactory Drug Aerosol Delivery with Acoustic Radiation
Authors: Abdollahzadeh Jamalabadi Mohammad Yaghoub , Xi Jinxiang
Published: June 2022

Nose-to-brain (N2B) drug delivery is a new approach to neurological disorder therapy as medications can bypass the blood-brain barrier and directly enter the brain. However, the delivery efficiency to the olfactory region using the conventional delivery method is impractically low because of the region’s secluded position in a convoluted nasal cavity. In this study, the acoustic radiation force was explored as an N2B delivery alternative in a wide frequency range of 10–100,000 Hz at an increment of 50 Hz. Numerical simulations of the particle deposition in the olfactory region of four nasal configurations were performed using COMSOL. Frequency analysis of the nasal cavities revealed that eigenfrequencies were often associated with a specific region with narrow passages and some eigenfrequencies exhibited an amendable pressure field to the olfactory region. Transient particle tracking was conducted with an acoustic inlet at 1 Pa, and a frequency spectrum of 10–100,000 Hz was imposed on the airflow, which carried the particles with acoustic radiation forces. It was observed that by increasing the pulsating wave frequency at the nostrils, the olfactory delivery efficiency reached a maximum in the range 11–15 kHz and decreased after that. The correlation of the olfactory delivery efficiency and instantaneous values of other parameters such as acoustic velocity and pressure in the frequency domain was examined.
ROCK and PDE-5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis
Authors: Lee Dong-Hun , Lee Ji Young , Hong Dong-Yong , Lee Eun Chae , Park Sang-Won , Jo Yu Na , Park Yu Jin , Cho Jae Young , Cho Yoo Jin , Chae Su Hyun , Lee Man Ryul , Oh Jae Sang
Published: June 2022

Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimer’s disease or vascular dementia and several other risk factors, including genetic factors. It is difficult to treat as its incidence continues to increase worldwide. Many studies have been performed concerning the treatment of this condition. Rho-associated kinase (ROCK) and phosphodiesterase-5 (PDE-5) are attracting attention as pharmacological treatments to improve the symptoms. This review discusses how ROCK and PDE-5 affect Alzheimer’s disease, vascular restructuring, and exacerbation of neuroinflammation, and how their inhibition helps improve cognitive function. In addition, the results of the animal behavior analysis experiments utilizing the Morris water maze were compared through meta-analysis to analyze the effects of ROCK inhibitors and PDE-5 inhibitors on cognitive function. According to the selection criteria, 997 publications on ROCK and 1772 publications on PDE-5 were screened, and conclusions were drawn through meta-analysis. Both inhibitors showed good improvement in cognitive function tests, and what is expected of the synergy effect of the two drugs was confirmed in this review.
Deep Learning-Based Computer-Aided Diagnosis of Rheumatoid Arthritis with Hand X-ray Images Conforming to Modified Total Sharp/van der Heijde Score
Authors: Wang Hao-Jan , Su Chi-Ping , Lai Chien-Chih , Chen Wun-Rong , Chen Chi , Ho Liang-Ying , Chu Woei-Chyn , Lien Chung-Yueh
Published: June 2022

Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease; early diagnosis and treatment are crucial for its management. Currently, the modified total Sharp score (mTSS) is widely used as a scoring system for RA. The standard screening process for assessing mTSS is tedious and time-consuming. Therefore, developing an efficient mTSS automatic localization and classification system is of urgent need for RA diagnosis. Current research mostly focuses on the classification of finger joints. Due to the insufficient detection ability of the carpal part, these methods cannot cover all the diagnostic needs of mTSS. Method: We propose not only an automatic label system leveraging the You Only Look Once (YOLO) model to detect the regions of joints of the two hands in hand X-ray images for preprocessing of joint space narrowing in mTSS, but also a joint classification model depending on the severity of the mTSS-based disease. In the image processing of the data, the window level is used to simulate the processing method of the clinician, the training data of the different carpal and finger bones of human vision are separated and integrated, and the resolution is increased or decreased to observe the changes in the accuracy of the model. Results: Integrated data proved to be beneficial. The mean average precision of the proposed model in joint detection of joint space narrowing reached 0.92, and the precision, recall, and F1 score all reached 0.94 to 0.95. For the joint classification, the average accuracy was 0.88, and the accuracy of severe, mild, and healthy reached 0.91, 0.79, and 0.9, respectively. Conclusions: The proposed model is feasible and efficient. It could be helpful for subsequent research on computer-aided diagnosis in RA. We suggest that applying the one-hand X-ray imaging protocol can improve the accuracy of mTSS classification model in determining mild disease if it is used in clinical practice.
Joint Cartilage in Long-Duration Spaceflight
Authors: Ganse Bergita , Cucchiarini Magali , Madry Henning
Published: June 2022

This review summarizes the current literature available on joint cartilage alterations in long-duration spaceflight. Evidence from spaceflight participants is currently limited to serum biomarker data in only a few astronauts. Findings from analogue model research, such as bed rest studies, as well as data from animal and cell research in real microgravity indicate that unloading and radiation exposure are associated with joint degeneration in terms of cartilage thinning and changes in cartilage composition. It is currently unknown how much the individual cartilage regions in the different joints of the human body will be affected on long-term missions beyond the Low Earth Orbit. Given the fact that, apart from total joint replacement or joint resurfacing, currently no treatment exists for late-stage osteoarthritis, countermeasures might be needed to avoid cartilage damage during long-duration missions. To plan countermeasures, it is important to know if and how joint cartilage and the adjacent structures, such as the subchondral bone, are affected by long-term unloading, reloading, and radiation. The use of countermeasures that put either load and shear, or other stimuli on the joints, shields them from radiation or helps by supporting cartilage physiology, or by removing oxidative stress possibly help to avoid OA in later life following long-duration space missions. There is a high demand for research on the efficacy of such countermeasures to judge their suitability for their implementation in long-duration missions.
Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder
Authors: Sauzeau Vincent , Beignet Julien , Bailly Christian
Published: June 2022

Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them—NSC23766 and EHT 1864—have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.
2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies
Authors: Raimondi Vittoria , Ciotti Giulia , Gottardi Michele , Ciccarese Francesco
Published: June 2022

The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML.
Why Does Psychotherapy Work and for Whom? Hormonal Answers
Authors: Fischer Susanne , Zilcha-Mano Sigal
Published: June 2022

The questions of for whom and why psychotherapy is effective have been the focus of five decades of research. Most of this knowledge is based on self-report measures. Following the biopsychosocial model of mental disorders, this article explores the potential of hormones in answering these questions. The literature on cortisol, oxytocin, and oestradiol in psychotherapy was systematically searched, focusing on (a) baseline hormonal predictors of who may benefit from psychotherapy and (b) hormonal changes as indicators of therapeutic change. The search was limited to depression and anxiety disorders. In sum, the findings show that, of all three hormones, the role of cortisol is most established and that both cortisol and oxytocin are implicated in psychotherapy, although a causal role is still waiting to be demonstrated. Moreover, there is a differential role of hormones in the psychotherapy of depression versus anxiety. The directions of research mapped in this article may elucidate how psychotherapy can be selected to match patients’ endocrine states and how hormonal levels can be manipulated to improve outcomes.
Increased Abundances of CD16+ Non-Classical Monocytes Accompany with Elevated Monocytic PD-L1 and CD4+ T Cell Disturbances in Oropharyngeal Cancer
Authors: Idel Christian , Polasky Christina , Ribbat-Idel Julika , Loyal Kristin , Perner Sven , Rades Dirk , Bruchhage Karl-Ludwig , Pries Ralph
Published: June 2022

Background: Patients with human papilloma virus (HPV)-related oropharyngeal cancer have a better prognosis than nonvirally associated patients, most likely because of better immune responses. Increased infiltration of T lymphocytes into the oropharyngeal tumor tissue has been observed, but the dynamics of circulating lymphocytes and monocytes are not fully understood. The aim of this study was to understand the population dynamics of circulating monocyte subsets in oropharyngeal cancer (OPC) patients with regard to the clinicopathological parameters and accompanying immunological consequences in view of the CD4/CD8 T cell subset composition, and the expression of checkpoint pathway proteins programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). Materials and Methods: The abundance of circulating monocyte subsets and peripheral blood CD4/CD8 T cells of oropharyngeal cancer patients and their PD-L1 and PD-1 expression levels were analyzed by flow cytometry. Results: The studied oropharyngeal cancer patients revealed heterogeneous individual redistributions of CD14++CD16− (classical), CD14++CD16+ (intermediate), and CD14dim+CD16+ (nonclassical) monocyte subsets compared with healthy donors. These differences in monocyte subset alterations were independent in patients with TNM or HPV status but entailed further immunological consequences. Increased percentages of nonclassical monocytes significantly correlated with increased levels of monocytic PD-L1 expression. We observed significantly decreased levels of CD4+ effector T cells, which were accompanied by increased CD4+ effector memory T cells in OPC patients compared with healthy donors, each having a stronger effect in patients with decreased levels of classical monocytes. Conclusion: We conclude that oropharyngeal cancer, as a malignancy from a lymphoid-tissue-rich anatomical region, has a strong systemic impact on the differentiation and regulation of circulating innate and adaptive immune cells. Further comprehensive investigations are required for the possible future usability of the described immunological alterations as bioliquid parameters for prognosis or therapy response prediction.
The Reduction in Microtubule Arrays Caused by the Dysplasia of the Non-Centrosomal Microtubule-Organizing Center Leads to a Malformed Organ of Corti in the Cx26-Null Mouse
Authors: Qiu Yue , Xu Kai , Xie Le , Chen Sen , Sun Yu
Published: June 2022

Mutations in the GJB2 gene account for approximately 20–50% of all non-syndromic hereditary deafness cases. The malformed organ of Corti (OC) was observed in different Cx26-null mouse models, which was mainly caused by the developmental arrest of pillar cells (PCs). However, the mechanism of developmental abnormalities in PCs caused by Cx26 deletion is still unclear. In this study, the ultrastructure of PCs at different postnatal days was observed in Cx26-null mice. Knockout of cochlear Cx26 led to the malformed assembly of non-centrosomal microtubule-organizing centers (MTOCs) far from the centrosome rather than near the centrosome. Additionally, the microtubule (MT) arrays emitted by abnormal non-centrosomal MTOCs were significantly reduced. In addition, we found that the protein expression of calmodulin-regulated, spectrin-associated protein2 (camsap2), a microtubule minus-end targeting protein associated with the organization of non-centrosomal MTs, was decreased in juvenile PCs in the Cx26-null group. Our results indicated that the malformation of non-centrosomal MTOCs in cochlear PCs might lead to the corresponding MTs’ failure to be captured and anchored in Cx26-null mice, which results in the deformity of OC. Additionally, this abnormal developmental process might be correlated with the reduced expression of camsap2 caused by Cx26 deletion in the early developmental stage.
Antihuman Endogenous Retrovirus Immune Response and Adaptive Dysfunction in Autism
Authors: Carta Alessandra , Manca Maria Antonietta , Scoppola Chiara , Simula Elena Rita , Noli Marta , Ruberto Stefano , Conti Marta , Zarbo Ignazio Roberto , Antonucci Roberto , Sechi Leonardo A. , Sotgiu Stefano
Published: June 2022

ASD is a neurodevelopmental disorder of unknown aetiology but with a known contribution of pathogenic immune-mediated mechanisms. HERVs are associated with several neuropsychiatric diseases, including ASD. We studied anti-HERV-W, -K and -H-env immune profiles in ASD children to analyse differences between their respective mothers and child/mother control pairs and possible correlations to ASD severity and loss of adaptive abilities. Of the 84 studied individuals, 42 children (23 ASD and 19 neurotypical) and their paired mothers underwent clinical and neuropsychological evaluations. ASD severity was analysed with standardised tests. Adaptive functioning was studied with ABAS-II and GAC index. Plasma anti-env responses of HERV-K, -H and -W were tested with indirect ELISA. ASD and neurotypical children did not differ in age, gender, comorbidities and anti-HERV responses. In children with ASD, anti-HERV levels were not correlated to ASD severity, while a significant inverse correlation was found between anti-HERV-W-248-262 levels and adaptive/social abilities. Upregulation of anti-HERV-W response correlates to dysfunctional social and adaptive competences in ASD but not in controls, suggesting anti-HERV response plays a role in the appearance of peculiar ASD symptoms.