bluuebunny/crossref_metadata_2025 huggingface dataset:
Health Risk Assessment From Heavy Metals Derived From Drinking Water and Rice, and Correlation With CKDu
Authors: Kulathunga Mudalige R. D. L. , Wijayawardena M. A. Ayanka , Naidu Ravi , Wimalawansa Sunil J. , Rahman Mohammad Mahmudur
Published: February 2022

Rice is the staple food of most Asians, including Sri Lankans. It is cultivated extensively in the dry zonal regions in Sri Lanka such as the Polonnaruwa district, where the prevalence of chronic kidney disease of unknown etiology (CKDu) is higher. We investigated the concentrations of potentially toxic heavy metal(loid)s in groundwater and locally produced rice and correlated their exposure with the prevalence of CKDu. We studied human health exposure risks such as total daily intake (TDI), hazard quotient, hazard index, and carcinogenic risk (CR) from the consumption of groundwater and rice. In well-water, the concentrations of heavy metal(loid)s, cadmium (Cd), arsenic (As), and lead (Pb) were below the World Health Organization (WHO) stipulated allowable limits. Except for Pb, contents of other heavy metal(loid) in all rice samples were lower than maximum permissible limits by the WHO (0.02 mg/kg). Twenty-three per cent (23%) of rice samples analyzed exceeded the permissible limit for TDI of Pb, and analysis of hazard index for Cd, As, and Pb revealed 26% of rice samples could result in a health risk through the consumption of rice in this population. Further, the outcome depicted no CR of Cd, As, and Pb by consuming rice in this study area. We recommended further studies and investigations to minimize or eliminate potential risks from chronic Pb exposure to consumers.
Perceptions and Responses of Diversified Farm Producers in the Northern Great Plains to the Early Stage of the COVID-19 Pandemic
Authors: Ebel Roland , Ahmed Selena , Warne Teresa , Moxley Alexandria , Grimberg Irene , Jarchow Meghann , Menalled Fabian D.
Published: February 2022

The initial months of the COVID-19 pandemic revealed unique vulnerabilities of the global food system with notable societal consequences, calling for the need to implement resilience strategies to support food security for all. The objective of this study was to elicit perceptions, experiences, and responses of producers of diversified farms in the Northern Great Plains of the United States to the early stage of the COVID-19 pandemic toward identifying factors for strengthening the resilience of agricultural production for supporting livelihoods and food security. Between May and August 2020, a cross-sectional online survey was administered to the emerging community of diversified farm managers in two rural U.S. states, Montana and South Dakota (n= 53), where monocropping and extensive livestock production are prevalent. About two-thirds of surveyed producers (68%) reported that they did not change their farming practices in response to the pandemic up until the survey period in Summer 2020. Almost three-quarters of producers (73%) indicated that access to commodities, farm inputs, and farm labor was not a concern for them during the early stage of the pandemic. Most surveyed producers (88%) were not concerned about their household food security and expressed confidence regarding a long-term increase in the demand for local food. However, almost half of surveyed producers (47%) reported that their anxiety increased because of the pandemic. Findings further highlight that small farms implemented a greater number of practices for enhancing ecological self-regulation while depending strongly on off-farm income compared to larger farms that were economically more autonomous. This study points to the promise of farm system diversification in strengthening the resilience of agricultural systems. We conclude by outlining pathways for increasing diversity on farms toward supporting food security during extreme food system shocks.
A Biased-Randomized Discrete-Event Algorithm for the Hybrid Flow Shop Problem with Time Dependencies and Priority Constraints
Authors: Laroque Christoph , Leißau Madlene , Copado Pedro , Schumacher Christin , Panadero Javier , Juan Angel A.
Published: February 2022

Based on a real-world application in the semiconductor industry, this article models and discusses a hybrid flow shop problem with time dependencies and priority constraints. The analyzed problem considers a production where a large number of heterogeneous jobs are processed by a number of machines. The route that each job has to follow depends upon its type, and, in addition, some machines require that a number of jobs are combined in batches before starting their processing. The hybrid flow model is also subject to a global priority rule and a “same setup” rule. The primary goal of this study was to find a solution set (permutation of jobs) that minimizes the production makespan. While simulation models are frequently employed to model these time-dependent flow shop systems, an optimization component is needed in order to generate high-quality solution sets. In this study, a novel algorithm is proposed to deal with the complexity of the underlying system. Our algorithm combines biased-randomization techniques with a discrete-event heuristic, which allows us to model dependencies caused by batching and different paths of jobs efficiently in a near-natural way. As shown in a series of numerical experiments, the proposed simulation-optimization algorithm can find solutions that significantly outperform those provided by employing state-of-the-art simulation software.
Czech Comparative Advantage in Agricultural Trade with Regard to EU-27: Main Developmental Trends and Peculiarities
Authors: Kuzmenko Elena , Rumankova Lenka , Benesova Irena , Smutka Lubos
Published: February 2022

The paper, based on RCA, LFI and GL indices, and logistic regression analysis, allowed us to track the dynamics of the comparative advantage/disadvantage of the Czech Republic in individual commodity aggregates in relation to individual EU partners, and to comprehend the role of the main production factors. The only production factor with a statistically significant effect is capital. Trade with countries richly endowed with agricultural land and capital, in most cases, appeared not favorable for the Czech Republic in terms of having a comparative advantage over them, if measured with LFI index. The values of the GL index disclosed that trade with these countries is mostly of an inter-industry character. The analysis revealed the following top-3 mostly competitive Czech aggregates: S3-08 (animal feed stuff), S3-06 (sugar and sugar preparations), along with S3-04 (cereals and cereal preparations). Some aggregates appeared to not have any comparative advantage: S3-01 (meat, meat preparations), S3-05 (vegetables and fruits), and S3-41 (animal oils and fats). Speaking of developmental trends, from 2000 to 2019 the Czech Republic has managed to improve its position in agri-food trade within the EU-27 by 43.81% if measured with LFI, and by 51.63% if measured with RCA. These positive changes also appeared to be statistically significant.
Improved Enzymatic Assay and Inhibition Analysis of Redox Membranotropic Enzymes, AtGALDH and TcGAL, Using a Reversed Micellar System
Authors: Chudin Andrey A. , Kudryashova Elena V.
Published: February 2022

Reversed micelles are helpful to solubilize otherwise insoluble membranotropic or membrane-bound enzymes in their functional form, thus enabling activity assay and inhibition analysis. However, in the case of redox enzymes, this task is further complicated by the necessity to select an appropriate electron-acceptor (EA) which, ideally, should be compatible with spectrophotometric measurements in reversed micelles. Here, we have identified such an EA and successfully used it in a reversed micellar environment to assay the activity of two homologous enzymes from mitochondria: l-galactone-1,4-lactone dehydrogenase (EC 1.3.2.3) from Arabidopsis thaliana (AtGALDH) and galactonolactone oxidase (EC 1.3.3.12) from Trypanosoma cruzi (TcGAL), differing in their membranotropic properties, with TcGAL being almost insoluble in water and particularly difficult to assay. Furthermore, we have demonstrated the possibility to use this assay for inhibition analysis, with an elucidation of the mechanism and inhibition parameters, which otherwise could not be possible. In order to perform inhibition analysis, we improved the approach for the determination of activity of such membrane enzymes based on a reversed micellar system as membrane matrix, necessary for the functioning of membrane enzymes. A number of electron acceptors (EA) were tested for AtGALDH and optimal conditions of activity determination for AtGALDH were found. The suggested method was successfully applied to the study of the inhibition of AtGALDH by lycorine, and the mixed competitive mechanism of inhibition of AtGALDH by lycorine was determined. The developed approach to inhibitor analysis was applied for TcGAL, insoluble in water membrane, and the method provides new opportunities for searching effective inhibitors that may be potential drugs. Indeed, galactonolactone oxidase from Trypanosoma cruzi (TcGAL) and AtGALDH are homologues, and the inhibition of TcGAL stops the vital biosynthesis of vitamin C in parasite Trypanosoma cruzi from causing Chagas disease. The approach proposed can be applied for the screening of inhibitors of AtGALDH and TcGAL, as well as to study properties of other membrane enzymes including determination of the mechanisms of inhibition, structure and catalytic properties, the impact of membrane components (for example lipids), and so on.
Carcass Quality Profiles and Associated Genomic Regions of South African Goat Populations Investigated Using Goat SNP50K Genotypes
Authors: Ncube Keabetswe Tebogo , Dzomba Edgar Farai , Hadebe Khanyisile , Soma Pranisha , Frylinck Lorinda , Muchadeyi Farai Catherine
Published: February 2022

Carcass quality includes a battery of essential economic meat traits that play a significant role in influencing farmer breed preferences. A preliminary study was undertaken to investigate the carcass quality and the associated genomic regions in a small nucleus of animals that are representative of South African goat genetic resources. Samples of the South African Boer (n = 14), Northern Cape Speckled (n = 14), Eastern Cape Xhosa Lob ear (n = 12), Nguni/Mbuzi (n = 13), and Village (n = 20) were genotyped using the Illumina goat SNP50K and were phenotyped for carcass quality traits. SA Boer goats had heavier warm and cold carcass weights (17.2 ± 2.3 kg and 16.3 ± 2.3 kg). Pella village goats raised under an intensive system had significantly (p < 0.05) heavier warm and cold carcass weights (9.9 ± 1.1 kg and 9.2 ± 1.2 kg) compared to the village goats that are raised extensively (9.1 ± 2.0 kg and 8.4 ± 1.9). A total of 40 SNPs located on chromosomes 6, 10, 12, 13, 19, and 21 were significantly associated with carcass traits at (−log10 [p < 0.05]). Candidate genes that were associated with carcass characteristics (GADD45G, IGF2R, GAS1, VAV3, CAPN8, CAPN7, CAPN2, GHSR, COLQ, MRAS, and POU1F1) were also observed. Results from this study will inform larger future studies that will ultimately find use in breed improvement programs.
Genomic Predictions of Phenotypes and Pseudo-Phenotypes for Viral Nervous Necrosis Resistance, Cortisol Concentration, Antibody Titer and Body Weight in European Sea Bass
Authors: Faggion Sara , Bertotto Daniela , Bonfatti Valentina , Freguglia Matteo , Bargelloni Luca , Carnier Paolo
Published: February 2022

In European sea bass (Dicentrarchus labrax L.), the viral nervous necrosis mortality (MORT), post-stress cortisol concentration (HC), antibody titer (AT) against nervous necrosis virus and body weight (BW) show significant heritability, which makes selective breeding a possible option for their improvement. An experimental population (N = 650) generated by a commercial broodstock was phenotyped for the aforementioned traits and genotyped with a genome-wide SNP panel (16,075 markers). We compared the predictive accuracies of three Bayesian models (Bayes B, Bayes C and Bayesian Ridge Regression) and a machine-learning method (Random Forest). The prediction accuracy of the EBV for MORT was approximately 0.90, whereas the prediction accuracies of the EBV and the phenotype were 0.86 and 0.21 for HC, 0.79 and 0.26 for AT and 0.71 and 0.38 for BW. The genomic prediction of the EBV for MORT used to classify the phenotype for the same trait showed moderate classification performance. Genome-wide association studies confirmed the polygenic nature of MORT and demonstrated a complex genetic structure for HC and AT. Genomic predictions of the EBV for MORT could potentially be used to classify the phenotype of the same trait, though further investigations on a larger experimental population are needed.
Enhancement of the Colorectal Chemopreventive and Immunization Potential of Northern Thai Purple Rice Anthocyanin Using the Biotransformation by β-Glucosidase-Producing Lactobacillus
Authors: Sirilun Sasithorn , Chaiyasut Chaiyavat , Pattananandecha Thanawat , Apichai Sutasinee , Sirithunyalug Jakkapan , Sirithunyalug Busaban , Saenjum Chalermpong
Published: February 2022

This study aimed to study the biotransformation of indigenous northern Thai purple rice using β-glucosidase-producing Lactobacillus (BGPL) to increase the content of bioactive anthocyanin for colorectal chemoprevention and immunization. BGPL, namely, Lactobacillus FR 332, was first isolated from Thai fermented foods. Indigenous northern Thai purple rice, namely, Khao’ Gam Leum-Phua (KGLP), was selected to study bioactive anthocyanin using biotransformation by L. plantarum FR332 according to the highest amounts of cyanidin-3-glucoside. The determination of anthocyanin quantities revealed that the highest cyanidin was detected after 12 h of biotransformation, corresponding to the highest β-glucosidase activity of L. plantarum FR332 and a decrease in cyanidin-3-glucoside. The anthocyanin extract, after 12 h of biotransformation, exhibited the most potent in vitro antioxidative activity. Additionally, it showed potent anti-inflammatory activity by inhibiting cyclooxygenase-2 (COX-2), nitric oxide, and inducible nitric oxide synthase (iNOS) production in interferon-γ-stimulated colon adenocarcinoma (HT-29) cells without exerting cytotoxicity. Moreover, it also showed a potent inhibitory effect on proinflammatory cytokine interleukin-6 (IL-6) secretion and an induction effect on anti-inflammatory cytokine IL-10 secretion. These documents highlight the potential to be used of the anthocyanin extract after 12 h of biotransformation by L. plantarum FR332 as a natural active pharmaceutical ingredient (NAPI) for colorectal chemoprevention and immunization.
Cybersecurity in the Internet of Things in Industrial Management
Authors: Raimundo Ricardo Jorge , Rosário Albérico Travassos
Published: February 2022

Nowadays, people live amidst the smart home domain, while there are business opportunities in industrial smart cities and healthcare. However, there are concerns about security. Security is central for IoT systems to protect sensitive data and infrastructure, whilst security issues have become increasingly expensive, in particular in Industrial Internet of Things (IIoT) domains. Nonetheless, there are some key challenges for dealing with those security issues in IoT domains: Applications operate in distributed environments such as Blockchain, varied smart objects are used, and sensors are limited, as far as machine resources are concerned. In this way, traditional security does not fit in IoT systems. The issue of cybersecurity has become paramount to the Internet of Things (IoT) and the Industrial Internet of Things (IIoT) in mitigating cybersecurity risk for organizations and end users. New cybersecurity technologies/applications present improvements for IoT security management. Nevertheless, there is a gap in the effectiveness of IoT cyber risk solutions. This review article discusses the literature trends around opportunities and threats in cybersecurity for IIoT, by reviewing 70 key articles discovered from a profound Scopus literature survey. It aims to present the current debate around the issue of IIoT rather than suggesting any particular technical solutions to solve network security problems.
On the Modeling and Analysis of Brittle Failure in Existing R/C Structures Due to Seismic Loads
Authors: Pardalopoulos Stylianos I. , Pantazopoulou Stavroula J. , Manolis George D.
Published: February 2022

Brittle failure is often observed in older reinforced concrete (R/C) buildings that have been designed prior to the 1980s following an earthquake event. Since this has ramifications on any subsequent repair protocol, it is important to quantify the remaining strength capacity for this class of building to determine a retrofit strategy. Following along these lines, an analytical-numerical methodology is presented for use as a third-tier seismic assessment which is based on a previously developed second-tier strength assessment criterion coming from a procedure known as Rapid Seismic Assessment (RSA). The assessment framework is performance-based, aiming to determine whether estimated local drift demands can be tolerated without failure developing along the load resistance path of substandard R/C buildings. This enables the development of guidelines for modeling all possible strength mechanisms that occur in the structural system of substandard R/C buildings. An application example using data provided by a benchmark experiment involving a full-scale R/C building helps to illustrate and then validate the proposed modeling procedures and establish their accuracy and efficiency for use by practicing engineers.
Multi-Modality Cardiovascular Imaging Assessment in Fabry Disease
Authors: Roy Ashwin , Mansour Mohamed , Oxborough David , Geberhiwot Tarekegn , Steeds Richard
Published: February 2022

Fabry disease (FD) is a rare X-linked lysosomal storage disorder manifesting as progressive multi-organ accumulation of sphingolipids due to deficiency in the enzyme α-Galactosidase A. Sphingolipid accumulation can take place in all cardiac cell types which manifests as left ventricular hypertrophy, microvascular ischaemia, conduction abnormalities, arrhythmia, heart failure, and valvular disease. The use of advanced cardiovascular imaging techniques have enabled clinicians to stage and prognosticate the disease and guide therapy. Transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) in conjunction are the hallmark imaging modalities to allow for this assessment. Traditionally, the assessment of cardiac involvement in FD was based on the assessment of maximal wall thickness (MWT) and the development of left ventricular hypertrophy (LVH). It is now understood that sphingolipid accumulation takes place before the development of LVH. Advances in techniques within TTE and CMR, particularly that of strain assessment and T1/T2 mapping, have meant that Fabry cardiomyopathy (FCM) can be diagnosed earlier in the disease process. This potentially provides a window for initiation of enzyme replacement therapy (ERT) at a stage where it is likely to have the most beneficial effect in reducing the high mortality associated with FCM. This review outlines the advances in multimodality imaging in staging and prognosticating FCM, as well as the applications of cardiac imaging in assessing symptoms and complications of FCM.
A System View to the Risks of COVID-19 Vaccination Projects
Authors: Sorooshian Shahryar , Abbaspour Afshin , Jahan Ali
Published: February 2022

The global vaccination program provides hope for ending the present worldwide pandemic. Due to the current pandemic, COVID-19 vaccines must be delivered and administered to communities once supplies are available. However, there are significant challenges in the sourcing, allocation, distribution, and uptake of vaccinations. A successful vaccination program would necessitate adequate risk management across the vaccination supply chain. This article has collected the predictable risks of the COVID-19 vaccines considered within the vaccine delivery system framework. The risks are presented based on relevant literature. Hence, this work’s framework is expected to contribute to better risk management of vaccination programs and similar future projects.
Generating Fine-Scale Aerosol Data through Downscaling with an Artificial Neural Network Enhanced with Transfer Learning
Authors: Wang Menglin , Franklin Meredith , Li Lianfa
Published: February 2022

Spatially and temporally resolved aerosol data are essential for conducting air quality studies and assessing the health effects associated with exposure to air pollution. As these data are often expensive to acquire and time consuming to estimate, computationally efficient methods are desirable. When coarse-scale data or imagery are available, fine-scale data can be generated through downscaling methods. We developed an Artificial Neural Network Sequential Downscaling Method (ASDM) with Transfer Learning Enhancement (ASDMTE) to translate time-series data from coarse- to fine-scale while maintaining between-scale empirical associations as well as inherent within-scale correlations. Using assimilated aerosol optical depth (AOD) from the GEOS-5 Nature Run (G5NR) (2 years, daily, 7 km resolution) and Modern-Era Retrospective analysis for Research and Applications, Version 2 (MERRA-2) (20 years, daily, 50 km resolution), coupled with elevation (1 km resolution), we demonstrate the downscaling capability of ASDM and ASDMTE and compare their performances against a deep learning downscaling method, Super Resolution Deep Residual Network (SRDRN), and a traditional statistical downscaling framework called dissever ASDM/ASDMTE utilizes empirical between-scale associations, and accounts for within-scale temporal associations in the fine-scale data. In addition, within-scale temporal associations in the coarse-scale data are integrated into the ASDMTE model through the use of transfer learning to enhance downscaling performance. These features enable ASDM/ASDMTE to be trained on short periods of data yet achieve a good downscaling performance on a longer time-series. Among all the test sets, ASDM and ASDMTE had mean maximum image-wise R2 of 0.735 and 0.758, respectively, while SRDRN, dissever GAM and dissever LM had mean maximum image-wise R2 of 0.313, 0.106 and 0.095, respectively.
Analysis of Regional Changes in Geodetic Mass Balance for All Caucasus Glaciers over the Past Two Decades
Authors: Tielidze Levan G. , Jomelli Vincent , Nosenko Gennady A.
Published: February 2022

Glaciers and snow in the Caucasus are major sources of runoff for populated places in many parts of this mountain region. These glaciers have shown a continuous area decrease; however, the magnitude of mass balance changes at the regional scale need to be further investigated. Here, we analyzed regional changes in surface elevation (or thickness) and geodetic mass balance for 1861 glaciers (1186.1 ± 53.3 km2) between 2000 and 2019 from recently published dataset and outlines of the Caucasus glacier inventory. We used a debris-covered glacier dataset to compare the changes between debris-free and debris-covered glaciers. We also used 30 m resolution ASTER GDEM (2011) to determine topographic details, such as aspect, slope, and elevation distribution of glaciers. Results indicate that the mean rate of glacier mass loss has accelerated from 0.42 ± 0.61 m of water equivalent per year (m w.e. a−1) over 2000–2010, to 0.64 ± 0.66 m w.e. a−1 over 2010–2019. This was 0.53 ± 0.38 m w.e. a−1 in 2000–2019. Mass loss rates differ between the western, central, and eastern Greater Caucasus, indicating the highest mean annual mass loss in the western section (0.65 ± 0.43 m w.e. a−1) in 2000–2019 and much lower in the central (0.48 ± 0.35 m w.e. a−1) and eastern (0.38 ± 0.37 m w.e. a−1) sections. No difference was found between the northern and southern slopes over the last twenty years corresponding 0.53 ± 0.38 m w.e. a−1. The observed decrease in mean annual geodetic mass balance is higher on debris-covered glaciers (0.66 ± 0.17 m w.e. a−1) than those on debris-free glaciers (0.49 ± 0.15 m w.e. a−1) between 2000 and 2019. Thickness change values in 2010–2019 were 1.5 times more negative (0.75 ± 0.70 m a−1) than those in 2000–2010 (0.50 ± 0.67 m a−1) in the entire region, suggesting an acceleration of ice thinning starting in 2010. A significant positive trend of May-September air temperatures at two selected meteorological stations (Terskol and Mestia) along with a negative trend of October-April precipitation might be responsible for the negative mass balances and thinning for all Caucasus glaciers over the study period. These results provide insight into the change processes of regional glaciers, which is key information to improve glaciological and hydrological projections in the Caucasus region.
Emission Ratios and Source Identification of VOCs in Moscow in 2019–2020
Authors: Berezina Elena , Moiseenko Konstantin , Vasileva Anastasia , Pankratova Natalia , Skorokhod Andrey , Belikov Igor , Belousov Valery
Published: February 2022

Measurements of CO and 15 volatile organic compounds (VOCs) at the IAP-RAS (A.M. Obukhov Institute of Atmospheric Physics) site located in the center of Moscow were analyzed. Acetaldehyde, ethanol, 1.3-butadiene, isoprene, toluene and C-8 aromatics were established to be the main ozone precursors in the observed area, providing up to 82% of the total ozone formation potential of the VOCs measured. Diurnal and seasonal variations of the compounds are discussed. The concentrations of anthropogenic VOCs (acetaldehyde, benzene, 1.3-butadiene, toluene, and C-8 aromatics) did not exceed their maximum permissible levels, reaching their maxima in summer and autumn in the morning and evening hours. Biogenic ethanol and isoprene were the highest in summer midday but their concentrations were low enough (up to 4 and 0.4 ppbv, respectively) due to small vegetation area around the site. Emission ratios (ERs) for the main ozone precursors—acetaldehyde, ethanol, 1.3-butadiene, isoprene, toluene, and C-8 aromatics—were estimated from two-sided linear regression fits using benzene and CO as tracers for anthropogenic emissions, with spatial and temporal filters being applied to account for the influence of chemistry and local emission sources. The best estimates of ERs were obtained using benzene as a reference species. Anthropogenic fractions of VOCs (AFs) were then estimated. As expected, acetaldehyde, toluene, 1.3-butadiene, and C8aromatics were entirely anthropogenic and emitted mainly from urban vehicle exhausts throughout the day, both in summer and in winter. AFs of isoprene and ethanol did not exceed 30% and 50% in summer, respectively, during both daytime and nighttime hours. In winter, the anthropogenic fractions of isoprene and ethanol were slightly higher (up to 35% and 60%, respectively).
Perturbation of One-Dimensional Time-Independent Schrödinger Equation with a Near-Hyperbolic Potential
Authors: Kim Byungbae , Jung Soon-Mo
Published: February 2022

The authors have recently investigated a type of Hyers–Ulam stability of one-dimensional time-independent Schrödinger equation with a symmetric parabolic potential wall. In this paper, we investigate a type of Hyers–Ulam stability of the Schrödinger equation with a near-hyperbolic potential.
The Role of Connexin Hemichannels in Inflammatory Diseases
Authors: Peng Bo , Xu Chengping , Wang Shuaiwei , Zhang Yijie , Li Wei
Published: February 2022

The connexin protein family consists of approximately 20 members, and is well recognized as the structural unit of the gap junction channels that perforate the plasma membranes of coupled cells and, thereby, mediate intercellular communication. Gap junctions are assembled by two preexisting hemichannels on the membranes of apposing cells. Non-junctional connexin hemichannels (CxHC) provide a conduit between the cell interior and the extracellular milieu, and are believed to be in a protectively closed state under physiological conditions. The development and characterization of the peptide mimetics of the amino acid sequences of connexins have resulted in the development of a panel of blockers with a higher selectivity for CxHC, which have become important tools for defining the role of CxHC in various biological processes. It is increasingly clear that CxHC can be induced to open by pathogen-associated molecular patterns. The opening of CxHC facilitates the release of damage-associated molecular patterns, a class of endogenous molecules that are critical for the pathogenesis of inflammatory diseases. The blockade of CxHC leads to attenuated inflammation, reduced tissue injury and improved organ function in human and animal models of about thirty inflammatory diseases and disorders. These findings demonstrate that CxHC may contribute to the intensification of inflammation, and serve as a common target in the treatments of various inflammatory diseases. In this review, we provide an update on the progress in the understanding of CxHC, with a focus on the role of these channels in inflammatory diseases.
Application of Three-Dimensional Digital Technology in Orthodontics: The State of the Art
Authors: Francisco Inês , Ribeiro Madalena Prata , Marques Filipa , Travassos Raquel , Nunes Catarina , Pereira Flávia , Caramelo Francisco , Paula Anabela Baptista , Vale Francisco
Published: February 2022

Three-dimensional technologies are one of the most recent and relevant advancements in the field of Dentistry. These systems, including intraoral scans, 3D imaging exams (CAT scan, CBCT and MRI), CAD/CAM 3D printing devices and 3D computer software, have enabled clinicians to greatly improve patient care along with reducing treatment planning time. The present descriptive study aims to explore possible applications of 3D technologies during the diagnosis, treatment plan, case monitoring and result assessment in orthodontics. The overall upgrade provided by these technologies can improve the clinicians’ workflow and effectiveness by simplifying conventional techniques considered to be especially arduous.
Parametric Optimization and Decision Support Model Framework for Life Cycle Cost Analysis and Life Cycle Assessment of Flexible Industrial Building Structures Integrating Production Planning
Authors: Reisinger Julia , Kugler Stefan , Kovacic Iva , Knoll Maximilian
Published: February 2022

Most industrial buildings have a very short lifespan due to frequently changing production processes. The load-bearing structure severely limits the flexibility of industrial buildings and is a major contributor to their costs, carbon footprint and waste. This paper presents a parametric optimization and decision support (POD) model framework that enables automated structural analysis and simultaneous calculation of life cycle cost (LCC), life cycle assessment (LCA), recycling potential and flexibility assessment. A method for integrating production planning into early structural design extends the framework to consider the impact of changing production processes on the footprint of building structures already at an early design stage. With the introduction of a novel grading system, design teams can quickly compare the performance of different building variants to improve decision making. The POD model framework is tested by means of a variant study on a pilot project from a food and hygiene production facility. The results demonstrate the effectiveness of the framework for identifying potential economic and environmental savings, specifying alternative building materials, and finding low-impact industrial structures and enclosure variants. When comparing the examined building variants, significant differences in the LCC (63%), global warming potential (62%) and flexibility (55%) of the structural designs were identified. In future research, a multi-objective optimization algorithm will be implemented to automate the design search and thus improve the decision-making process.
Novel Repositioning Therapy for Drug-Resistant Glioblastoma: In Vivo Validation Study of Clindamycin Treatment Targeting the mTOR Pathway and Combination Therapy with Temozolomide
Authors: Eda Takeyoshi , Okada Masayasu , Ogura Ryosuke , Tsukamoto Yoshihiro , Kanemaru Yu , Watanabe Jun , On Jotaro , Aoki Hiroshi , Oishi Makoto , Takei Nobuyuki , Fujii Yukihiko , Natsumeda Manabu
Published: February 2022

Multimodal therapy including surgery, radiation treatment, and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to examine the signal activation patterns in GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose-dependent manner. These effects on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of the O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1)-positive cells within the tumor. These results suggest that CLD suppressed GBM cell growth by inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.
GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival
Authors: Petrusca Daniela N. , Mulcrone Patrick L. , Macar David A. , Bishop Ryan T. , Berdyshev Evgeny , Suvannasankha Attaya , Anderson Judith L. , Sun Quanhong , Auron Philip E. , Galson Deborah L. , Roodman G. David
Published: February 2022

Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5’ end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.
Disparities in Lung Cancer: miRNA Isoform Characterization in Lung Adenocarcinoma
Authors: Distefano Rosario , Nigita Giovanni , Le Patricia , Romano Giulia , Acunzo Mario , Nana-Sinkam Patrick
Published: February 2022

Despite the development of targeted therapeutics, immunotherapy, and strategies for early detection, lung cancer carries a high mortality. Further, significant racial disparities in outcomes exist for which the molecular drivers have yet to be fully elucidated. The growing field of Epitranscriptomics has introduced a new layer of complexity to the molecular pathogenesis of cancer. RNA modifications can occur in coding and non-coding RNAs, such as miRNAs, possibly altering their gene regulatory function. The potential role for such modifications as clinically informative biomarkers remains largely unknown. Here, we concurrently profiled canonical miRNAs, shifted isomiRs (templated and non-templated), and miRNAs with single-point modification events (RNA and DNA) in White American (W) and Black or African American (B/AA) lung adenocarcinoma (LUAD) patients. We found that while most deregulated miRNA isoforms were similar in W and B/AA LUAD tissues compared to normal adjacent tissues, there was a subgroup of isoforms with deregulation according to race. We specifically investigated an edited miRNA, miR-151a-3p with an A-to-I editing event at position 3, to determine how its altered expression may be associated with activation of divergent biological pathways between W and B/AA LUAD patients. Finally, we identified distinct race-specific miRNA isoforms that correlated with prognosis for both Ws and B/AAs. Our results suggested that concurrently profiling canonical and non-canonical miRNAs may have potential as a strategy for identifying additional distinct biological pathways and biomarkers in lung cancer.
Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors
Authors: Watanabe Hirofumi , Fujishima Fumiyoshi , Komoto Izumi , Imamura Masayuki , Hijioka Susumu , Hara Kazuo , Yatabe Yasushi , Kudo Atsushi , Masui Toshihiko , Tsuchikawa Takahiro , Sakamoto Kazuhiro , Shiga Hisashi , Nakamura Tomohiro , Nakaya Naoki , Motoi Fuyuhiko , Unno Michiaki , Sasano Hironobu
Published: February 2022

Somatostatin analogues (SSAs) are widely used to treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Somatostatin receptor 2 (SSTR2) immunoreactivity serves as a predictive marker of the therapeutic efficacy of SSAs in pancreatic NETs. However, SSTR2 expression profiles in tumor cells and their association with the therapeutic efficacy of SSAs remains virtually unknown in gastrointestinal NETs (GI-NETs). Therefore, we evaluated the association between SSTR2 immunoreactivity and embryological origin and proliferative activity in 132 resected surgical tissues of GI-NETs. The correlation between SSAs’ therapeutic efficacy and SSTR2 immunoreactivity was evaluated in 14 GI-NETs treated with SSAs. SSTR2 immunoreactivity was evaluated using Volante scores, immunoreactive scores, and digital image analysis (DIA). SSTR2 immunoreactivity was significantly negatively and positively correlated with the Ki-67 labeling index in foregut and hindgut NETs, respectively. In the normal mucosa, neuroendocrine cells in the rectum had significantly lower positive rates of SSTR2 than those in the stomach and duodenum. SSTR2 expression profiles in GI-NETs could differ by primary sites, while the difference of those between foregut and hindgut NETs might be derived from the SSTR2 status of normal neuroendocrine cell counterparts. In addition, DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs.
Dissecting the Mechanism of Action of Spiperone—A Candidate for Drug Repurposing for Colorectal Cancer
Authors: Antona Annamaria , Varalda Marco , Roy Konkonika , Favero Francesco , Mazzucco Eleonora , Zuccalà Miriam , Leo Giovanni , Soggia Giulia , Bettio Valentina , Tosi Martina , Gaggianesi Miriam , Riva Beatrice , Reano Simone , Genazzani Armando , Manfredi Marcello , Stassi Giorgio , Corà Davide , D’Alfonso Sandra , Capello Daniela
Published: February 2022

Approximately 50% of colorectal cancer (CRC) patients still die from recurrence and metastatic disease, highlighting the need for novel therapeutic strategies. Drug repurposing is attracting increasing attention because, compared to traditional de novo drug discovery processes, it may reduce drug development periods and costs. Epidemiological and preclinical evidence support the antitumor activity of antipsychotic drugs. Herein, we dissect the mechanism of action of the typical antipsychotic spiperone in CRC. Spiperone can reduce the clonogenic potential of stem-like CRC cells (CRC-SCs) and induce cell cycle arrest and apoptosis, in both differentiated and CRC-SCs, at clinically relevant concentrations whose toxicity is negligible for non-neoplastic cells. Analysis of intracellular Ca2+ kinetics upon spiperone treatment revealed a massive phospholipase C (PLC)-dependent endoplasmic reticulum (ER) Ca2+ release, resulting in ER Ca2+ homeostasis disruption. RNA sequencing revealed unfolded protein response (UPR) activation, ER stress, and induction of apoptosis, along with IRE1-dependent decay of mRNA (RIDD) activation. Lipidomic analysis showed a significant alteration of lipid profile and, in particular, of sphingolipids. Damage to the Golgi apparatus was also observed. Our data suggest that spiperone can represent an effective drug in the treatment of CRC, and that ER stress induction, along with lipid metabolism alteration, represents effective druggable pathways in CRC.
Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor
Authors: Sundaramurthi Husvinee , García-Mulero Sandra , Tonelotto Valentina , Slater Kayleigh , Marcone Simone , Piulats Josep M. , Watson Ronald William , Tobin Desmond J. , Jensen Lasse D. , Kennedy Breandán N.
Published: February 2022

Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time- and dose-dependent manner (p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.
Lifespan Increase of Podospora anserina by Oleic Acid Is Linked to Alterations in Energy Metabolism, Membrane Trafficking and Autophagy
Authors: Schürmanns Lea , Hamann Andrea , Osiewacz Heinz D.
Published: February 2022

The maintenance of cellular homeostasis over time is essential to avoid the degeneration of biological systems leading to aging and disease. Several interconnected pathways are active in this kind of quality control. One of them is autophagy, the vacuolar degradation of cellular components. The absence of the sorting nexin PaATG24 (SNX4 in other organisms) has been demonstrated to result in impairments in different types of autophagy and lead to a shortened lifespan. In addition, the growth rate and the size of vacuoles are strongly reduced. Here, we report how an oleic acid diet leads to longevity of the wild type and a PaAtg24 deletion mutant (ΔPaAtg24). The lifespan extension is linked to altered membrane trafficking, which abrogates the observed autophagy defects in ΔPaAtg24 by restoring vacuole size and the proper localization of SNARE protein PaSNC1. In addition, an oleic acid diet leads to an altered use of the mitochondrial respiratory chain: complex I and II are bypassed, leading to reduced reactive oxygen species (ROS) production. Overall, our study uncovers multiple effects of an oleic acid diet, which extends the lifespan of P. anserina and provides perspectives to explain the positive nutritional effects on human aging.
Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain
Authors: Sanchez-Gonzalez Rosario , Koupourtidou Christina , Lepko Tjasa , Zambusi Alessandro , Novoselc Klara Tereza , Durovic Tamara , Aschenbroich Sven , Schwarz Veronika , Breunig Christopher T. , Straka Hans , Huttner Hagen B. , Irmler Martin , Beckers Johannes , Wurst Wolfgang , Zwergal Andreas , Schauer Tamas , Straub Tobias , Czopka Tim , Trümbach Dietrich , Götz Magdalena , Stricker Stefan H. , Ninkovic Jovica
Published: February 2022

The oligodendrocyte progenitors (OPCs) are at the front of the glial reaction to the traumatic brain injury. However, regulatory pathways steering the OPC reaction as well as the role of reactive OPCs remain largely unknown. Here, we compared a long-lasting, exacerbated reaction of OPCs to the adult zebrafish brain injury with a timely restricted OPC activation to identify the specific molecular mechanisms regulating OPC reactivity and their contribution to regeneration. We demonstrated that the influx of the cerebrospinal fluid into the brain parenchyma after injury simultaneously activates the toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways, leading to increased OPC proliferation and thereby exacerbated glial reactivity. These pathways were critical for long-lasting OPC accumulation even after the ablation of microglia and infiltrating monocytes. Importantly, interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated reactive gliosis, increased new neuron recruitment, and improved tissue restoration.
Perspectives in Prevention of Biofilm for Medical Applications
Authors: Lisoń Julia , Taratuta Anna , Paszenda Zbigniew , Szindler Magdalena , Basiaga Marcin
Published: February 2022

The opportunity of decreasing the development of biofilm on the implant surface is one of the biggest research problems. It is connected with the existing prevention of microorganism hyperplasia. The application of numerous modifications is concerned with surface treatments leading to minimizing bacterial colonization. In the case of non-use antibacterial therapy, this leads to tissue infection. It can lead to a decreased opportunity to fight infection using antibiotherapy. One way is to decrease the increasing biofilm application which requires a method of modification. These techniques ensure properties like homogeneity or repeatability. The structure and chemical composition are changed with methods like CVD (Chemical Vapor Deposition), PVD (Physical Vapor Deposition), sol–gel, or ALD (Atomic Layer Deposition). Antibacterial properties of metals are connected with their impact on proteins and the nuclear proliferation of fibroblasts, causing improvement in biocompatibility and also growth corrosion resistance, and the decline of biofilm adhesion. The prevention of biofilm with medicines and antibiotics is a crowded-out treatment. Traditional methods of preventing biofilm are based on compounds that kill or inhibit the growth of the microbes but at the same time lead to frequent development of resistance to antibiotics. This review summarizes the current knowledge of reducing and preventing the creation of biofilm.