bluuebunny/crossref_metadata_2025 huggingface dataset:
An Improved Crystal Structure Algorithm for Engineering Optimization Problems
Authors: Wang Wentao , Tian Jun , Wu Di
Published: December 2022

Crystal Structure Algorithm (CryStAl) is a new meta-heuristic algorithm, and it has been studied by many scholars because of its wide adaptability and the fact that there is no need to set parameters in advance. An improved crystal structure algorithm (GLCryStAl) based on golden sine operator and Levy flight is designed in this paper. The algorithm makes good use of the relationship between the golden sine operator and the unit circle to make the algorithm exploration space more comprehensive, and then gradually narrows the search space in the iterative process, which can effectively speed up the convergence rate of the algorithm. At the same time, a Levy operator is introduced to help the algorithm effectively get rid of the attraction of local optimal value. To evaluate the performance of GLCryStAl, 12 classic benchmark functions and eight CEC2017 test functions were selected to design a series of comparative experiments. In addition, the experimental data of these algorithms are analyzed using the Wilcoxon and Friedman tests. Through these two tests, it can be found that GLCryStAl has significant advantages over other algorithms. Finally, this paper further tests the optimization performance of GLCryStAl in engineering design. GLCryStAl was applied to optimize pressure vessel design problems and tension/compression spring design problems. The optimization results show that GLCryStAl is feasible and effective in optimizing engineering design.
Towards Real-Time Warning and Defense Strategy AI Planning for Cyber Security Systems Aided by Security Ontology
Authors: Liu Yingze , Guo Yuanbo
Published: December 2022

Cyber security systems generally have the phenomena of passive defense and low-efficiency early warnings. Aiming at the above problems, this study proposes a real-time warning and plans an AI defense strategy for a cyber security system aided by a security ontology. First, we design a security defense ontology that integrates attack graphs, general purpose and domain-specific knowledge bases, and on this basis, we (1) develop an ontology-driven method of early warnings of real-time attacks, which supports non-intrusive scanning attack detection and (2) combine artificial intelligence planning and bounded rationality to recommend and automatically execute defense strategies in conventional defense scenarios. A case study has been performed, and the results indicate that: (1) the proposed method can quickly analyze network traffic data for real-time warnings, (2) the proposed method is highly feasible and has the ability to implement defense strategies autonomously, and (3) the proposed method performs the best, with a 5.4–11.4% increase in defense effectiveness against the state-of-the-art counterparts considering the APT29 attack. Overall, the proposed method holds the potential to increase the defense effectiveness against cyberattacks under high computing resource constraints.
Parallelly Running and Privacy-Preserving k-Nearest Neighbor Classification in Outsourced Cloud Computing Environments
Authors: Park Jeongsu , Lee Dong Hoon
Published: December 2022

Classification is used in various areas where k-nearest neighbor classification is the most popular as it produces efficient results. Cloud computing with powerful resources is one reliable option for handling large-scale data efficiently, but many companies are reluctant to outsource data due to privacy concerns. This paper aims to implement a privacy-preserving k-nearest neighbor classification (PkNC) in an outsourced environment. Existing work proposed a secure protocol (SkLE/SkSE) to compute k data with the largest/smallest value privately, but this work discloses information. Moreover, SkLE/SkSE requires a secure comparison protocol, and the existing protocols also contain information disclosure problems. In this paper, we propose a new secure comparison and SkLE/SkSE protocols to solve the abovementioned information disclosure problems and implement PkNC with these novel protocols. Our proposed protocols disclose no information and we prove the security formally. Then, through extensive experiments, we demonstrate that the PkNC applying the proposed protocols is also efficient. Especially, the PkNC is suitable for big data analysis to handle large amounts of data, since our SkLE/SkSE is executed for each dataset in parallel. Although the proposed protocols do require efficiency sacrifices to improve security, the running time of our PkNC is still significantly more efficient compared with previously proposed PkNCs.
Experimental and Numerical Dynamic Investigation of an ORC System for Waste Heat Recovery Applications in Transportation Sector
Authors: Marchionni Matteo , Fatigati Fabio , Di Bartolomeo Marco , Di Battista Davide , Petrollese Mario
Published: December 2022

ORC power units represent a promising technology for the recovery of waste heat in Internal Combustion Engines (ICEs), allowing to reduce emissions while keeping ICE performance close to expectations. However, the intrinsic transient nature of exhaust gases represents a challenge since it leads ORCs to often work in off-design conditions. It then becomes relevant to study their transient response to optimize performance and prevent main components from operating at inadequate conditions. To assess this aspect, an experimental dynamic analysis was carried out on an ORC-based power unit bottomed to a 3 L Diesel ICE. The adoption of a scroll expander and the control of the pump revolution speed allow a wide operability of the ORC. Indeed, the refrigerant mass flow rate can be adapted according to the exhaust gas thermal power availability in order to increase thermal power recovery from exhaust gases. The experimental data confirmed that when the expander speed is not regulated, it is possible to control the cycle maximum pressure by acting on the refrigerant flow rate. The experimental data have also been used to validate a model developed to extend the analysis beyond the experimental operating limits. It was seen that a 30% mass flow rate increase allowed to raise the plant power from 750 W to 830 W.
Fault-Tolerant Secure Data Aggregation Schemes in Smart Grids: Techniques, Design Challenges, and Future Trends
Authors: Khan Hayat Mohammad , Khan Abid , Khan Basheir , Jeon Gwanggil
Published: December 2022

Secure data aggregation is an important process that enables a smart meter to perform efficiently and accurately. However, the fault tolerance and privacy of the user data are the most serious concerns in this process. While the security issues of Smart Grids are extensively studied, these two issues have been ignored so far. Therefore, in this paper, we present a comprehensive survey of fault-tolerant and differential privacy schemes for the Smart Gird. We selected papers from 2010 to 2021 and studied the schemes that are specifically related to fault tolerance and differential privacy. We divided all existing schemes based on the security properties, performance evaluation, and security attacks. We provide a comparative analysis for each scheme based on the cryptographic approach used. One of the drawbacks of existing surveys on the Smart Grid is that they have not discussed fault tolerance and differential privacy as a major area and consider them only as a part of privacy preservation schemes. On the basis of our work, we identified further research areas that can be explored.
Characterization of Sulfides in Atmospheric Residue Fractions Using Selective Oxidation Followed by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry
Authors: Cui Wenlong , Zhao Chenze , Zhu Qingqing , Wang Cheli
Published: December 2022

An improved analytical method was developed for identifying sulfide compounds from aromatic fractions in Lungu atmospheric residue (LGAR). Sulfides in residue aromatics were selectively oxidized into sulfoxides using tetrabutyl ammonium periodate (TBAP) and identified by positive-ion Electrospray Ionization Source (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Results showed that sulfides with lower polarity in LGAR aromatics could effectively ionize in ESI using this approach. Additionally, the oxidized sulfides were mainly S1 and S2 class species. The most abundant oxidation-generated sulfoxides O1S1 and O1S2 in LGAR aromatics had DBE values of 3~10 and 8~12, respectively. The S2 class species, whose condensation degree was higher than that of S1, were likely in the form of containing both cyclic sulfides and thiophenic compounds.
Effect of Stress on Variations in the Magnetic Field of Ferromagnetic Steel under a Constant DC Magnetic Field
Authors: Yang Bin , Gao Yang , Liu Lin , Liu Zhifeng , Yu Yue , Wang Ruimin
Published: December 2022

In this paper, variations in the normal component of the magnetic field BZ on the surface of Q195 steel specimens produced by simultaneous application of noncoaxial DC magnetic field and stress were studied by tensile tests. It was found that there was no shift in the direction of BZ variations when the specimens were magnetized parallel to stress, whereas the direction of BZ variations shifted a slight angle relative to the DC magnetic field when the specimens were magnetized perpendicular to stress. The amplitude of BZ increased with stress from 0 MPa to 120 MPa when the stress was parallel to the DC magnetic field. On the contrary, the amplitude of BZ decreased with stress from 0 MPa to 120 MPa when the stress was perpendicular to the DC magnetic field. The mechanisms underlying the experimental characteristics are also discussed. This research provides the possibility for quantitative inspection of the stress in ferromagnetic steels using surface magnetic field measurements.
Applicability of Dynamic Inflow Models of HAWT in Yawed Flow Conditions
Authors: Hur Chihoon , Ferreira Carlos , Schepers Gerard
Published: December 2022

Horizontal axis wind turbines (HAWTs) experience yaw misalignments due to the physical limitations of yaw controllers and various novel active yaw controls. Moreover, the motion of floating offshore wind turbines (FOWTs) accelerates yaw misalignment. The blade element momentum (BEM) method is widely used due to its computational efficiency for the design of HAWTs. Momentum theory, the basis of BEM, assumes steady flow and uniform induction field at the disc. Those assumptions are relaxed by engineering models to capture yaw and unsteady effects. Current yaw engineering models, however, are inaccurate since they do not capture the asymmetric wake expansion effect. Dynamic inflow models have been developed for non-yawed flow. Furthermore, the AVATAR project shows that BEM using fully coupled engineering models, the current yaw, dynamic inflow and various engineering models, suffers from significant deficiencies. This purpose of this paper, therefore, is to investigate dynamic effects for yawed flow, and determine if current dynamic inflow models are applicable in yawed conditions. The Glauert’s modified momentum theory is applied to dynamic inflow models to couple the two models. Among all coupled models, Øye, Yu PWVM and Yu FWVM DIM can capture asymmetric trends. However, the results show the significant deficiencies in phase delay on the actuator disc.
Refurbishment of Natural Gas Pipelines towards 100% Hydrogen—A Thermodynamic-Based Analysis
Authors: Klopčič Nejc , Stöhr Thomas , Grimmer Ilena , Sartory Markus , Trattner Alexander
Published: December 2022

Hydrogen is a key enabler of a sustainable society. Refurbishment of the existing natural gas infrastructure for up to 100% H2 is considered one of the most energy- and resource-efficient energy transportation methods. The question remains whether the transportation of 100% H2 with reasonable adaptions of the infrastructure and comparable energy amounts to natural gas is possible. The well-known critical components for refurbishment, such as increased compressor power, reduced linepack as well as pipeline transport efficiencies, and their influencing factors were considered based on thermodynamic calculations with a step-by-step overview. A H2 content of 20–30% results in comparable operation parameters to pure natural gas. In addition to transport in pipelines, decentralized H2 production will also play an important role in addressing future demands.
Preparation and Structural Properties of Bacterial Nanocellulose Obtained from Beetroot Peel Medium
Authors: Beluhan Sunčica , Herceg Filip , Leboš Pavunc Andreja , Djaković Senka
Published: December 2022

The aim of the present study was to investigate structural modifications and physicochemical properties of bacterial nanocellulose (BNC) pellicles produced statically in a beetroot peel medium as a mixture of C-sources (8% sucrose, 2% glucose, and 0.86% fructose). Characteristics of these BNC samples were compared to those produced using a chemically defined and modified Hestrin–Schramm medium with 3% (w/v) glucose, fructose, and sucrose as sole carbon sources. Compared with the beetroot peel medium, where 11.57 g/L BNC (wet weight) was obtained, glucose gave the highest BNC yield (13.07 g/L), sucrose 10.55 g/L, and fructose 7.9 g/L. FT-IR spectra showed almost identical chemical profiles assigned to cellulose I. XRD analysis revealed that the BNC produced in beetroot peel medium had a larger crystallite size than other BNC samples. The crystallinity index of beetroot peel BNC was higher than that of Hestrin–Schramm BNC. The water-holding capacity, water release rate, and iodine sorption value from the beetroot peel medium were greater than those of other BNCs. Furthermore, as there is a necessity today to find cheaper carbon sources to obtain valuable products at a lower cost, beetroot peels represent an interesting alternative to producing BNC as a new functional material for industrial applications.
Multi-Parameter Optimization Design of Axial-Flow Pump Based on Orthogonal Method
Authors: Dai Zhenxing , Tan Lei , Han Bingfu , Han Suyang
Published: December 2022

The axial-flow pump is a widely used piece of general machinery which consumes large amounts of energy. In this study, an axial-flow pump with the specific speed of 536 is firstly designed and experimentally measured; then, the orthogonal method is employed to conduct the energy performance optimization. Five optimization parameters, including hub control point, hub stagger angle, shroud stagger angle, camber angle and centroid position were set with four levels. Sixteen individual pumps were designed according to the orthogonal method; then, a numerical simulation was implemented to obtain the energy performance and flow pattern. Results showed that the shroud stagger angle has the maximum influence on the pump head and efficiency, and the hub stagger angle and camber angle are also very important. At a design point of flow rate 70 kg/s, the efficiency of the optimal pump is 86.29%, which improved by 2.05% in comparison with the baseline pump. The pressure gradient of the optimal pump from blade inlet to outlet becomes more fluent than that of baseline pump, and the low-velocity region of the optimal pump at the blade head shrinks, compared to that of the baseline pump.
Chemical Damage Constitutive Model Establishment and the Energy Analysis of Rocks under Water–Rock Interaction
Authors: Xu Qi , Tian Angran , Luo Xinyu , Liao Xin , Tang Qiang
Published: December 2022

The physical and mechanical properties of rocks can be reduced significantly by an acidic environment, resulting in engineering weaknesses, such as building foundation instability, landslides, etc. In order to investigate the mechanical properties of rocks after hydrochemical erosion, a chemical damage constitutive model was established and used to analyze chemical damage variables and energy transformation. It is assumed that the strength of the rock elements obeyed Weibull distribution, considering the nonuniformity of rock. The chemical damage variable was proposed according to the load-bearing volume changes in the rock under water–rock chemical interactions. The chemical damage constitutive model was derived from coupling the mechanical damage under the external load and the chemical damage under hydrochemical erosion. In order to verify the accuracy of the model, semi-immersion experiments and uniaxial compression experiments of black sandy dolomite were carried out with different iron ion concentrations. Compared with the experimental data, the chemical damage constitutive model proposed could predict the stress–strain relationship reasonably well after water–rock interaction. The effects of water–rock interaction on the rock were a decrease in peak stress and an increase in peak strain. The peak strain increased by 4.96–29.58%, and the deterioration rate of peak strength was 0.19–4.18%. The energy transformation of the deterioration process was analyzed, and the results showed that the decrease in releasable elastic energy, Ue, is converted into dissipated energy, Ud, after hydrochemical erosion.
Willingness to Pay (WTP) for COVID-19 Vaccine Booster Dose and Its Determinants in Indonesia
Authors: Harapan Harapan , Sallam Malik , Fathima Raisha , Kusuma Hendrix Indra , Anwar Samsul , Nalapraya Widhy Yudistira , Wibowo Adityo , Kumara Wati Ketut Dewi , Medina Ayunda , Defrita Anna Hanifa , Astri Yesi , Prasetyowati Arie , Nurfarahin Nurfarahin , Khusna Afriyani , Oktariana Setya , Anwar Sarifuddin , Yussar Milza Oka , Khotimah Siti , Maria Nainggolan Bahagia Willibrordus , Amalia Badri Putri Rizki , Argarini Raden , Winardi Wira , Sharun Khan , Indah Rosaria , Rajamoorthy Yogambigai , Wagner Abram L. , Mudatsir Mudatsir
Published: December 2022

Willingness to pay (WTP) for booster doses of coronavirus disease 2019 (COVID-19) vaccines is an under studied research topic. Therefore, the current study aimed to investigate the WTP for the booster doses of COVID-19 vaccines and its predictors in Indonesia using an online survey distributed all over the provinces of this low-middle-income country. The WTP was evaluated using a basic dichotomous contingent valuation approach, and its associated determinants were evaluated using a linear regression model. Out of 2935 responders, 66.2% (1942/2935) were willing to pay for a booster dose of the COVID-19 vaccine. The majority of respondents (63.5%) were willing to pay within a price range of 100,000–500,000 Indonesian rupiah (IDR), i.e., USD 6.71–33.57. Being older than 40 years, having a higher educational level, having a higher income, knowing and understanding that booster doses were important, and having a vaccine status that is certified halal (permissible in Islamic law), were all associated with a higher WTP for the booster dose of COVID-19 vaccines. The study findings imply that the WTP for a booster dose of COVID-19 vaccination in Indonesia is lower compared to acceptance of vaccines provided free of charge. This WTP data can be utilized to develop a pricing scheme for the booster doses of COVID-19 vaccination in the country with potential benefits in other low-income countries. The government may be required to provide subsidies for the herd immunity vaccination process to proceed as anticipated. Furthermore, the public community must be educated on the importance of vaccination as well as the fact that the COVID-19 epidemic is far from being over.
Synthesis, DFT, Biological and Molecular Docking Analysis of Novel Manganese(II), Iron(III), Cobalt(II), Nickel(II), and Copper(II) Chelate Complexes Ligated by 1-(4-Nitrophenylazo)-2-naphthol
Authors: Alghuwainem Yousef A. A. , El-Lateef Hany M. Abd , Khalaf Mai M. , Amer Amer A. , Abdelhamid Antar A. , Alzharani Ahmed A. , Alfarsi Anas , Shaaban Saad , Gouda Mohamed , Abdou Aly
Published: December 2022

Novelmanganese(II), iron(III), cobalt(II), nickel(II), and copper(II) chelates were synthesized and studied using elemental analysis (EA), infrared spectroscopy, mass spectrometry, ultraviolet-visible spectroscopy, and conductivity, as well as magnetic measurements and thermogravimetric analysis (TG). The azo-ligand 1-[(4-nitrophenyl)diazenyl]-2-naphthol (HL) chelates to the metal ions via the nitrogen and oxygen centers of the azo group and the hydroxyl, respectively. The amounts of H2O present and its precise position were identified by thermal analysis. Density functional theory (DFT) was employed to theoretically elucidate the molecular structures of the ligand and the metal complexes. Furthermore, the quantum chemical parameters were also evaluated. The antimicrobial properties were evaluated against a group of fungal and bacterial microbes. Interestingly, the bioactivity of the complexes is enhanced compared to free ligands. Within this context, the CuL complex manifested the lowest activity, whereas the FeL complex had the greatest. Molecular docking was used to foretell the drugs’ binding affinity for the structure of Escherichia coli (PDB ID: 1hnj). Protein-substrate interactions were resolved, and binding energies were accordingly calculated.
CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy
Authors: Bogacka Joanna , Pawlik Katarzyna , Ciapała Katarzyna , Ciechanowska Agata , Mika Joanna
Published: December 2022

Chemokines and their receptors participate in many biological processes, including the modulation of neuroimmune interactions. Approximately fifty chemokines are distinguished in humans, which are classified into four subfamilies based on the N-terminal conserved cysteine motifs: CXC, CC, C, and CX3C. Chemokines activate specific receptors localized on the surface of various immune and nervous cells. Approximately twenty chemokine receptors have been identified, and each of these receptors is a seven-transmembrane G-protein coupled receptor. Recent studies provide new evidence that CC chemokine receptor 4 (CCR4) is important in the pathogenesis of many diseases, such as diabetes, multiple sclerosis, asthma, dermatitis, and cancer. This review briefly characterizes CCR4 and its ligands (CCL17, CCL22, and CCL2), and their contributions to immunological and neoplastic diseases. The review notes a significant role of CCR4 in nociceptive transmission, especially in painful neuropathy, which accompanies many diseases. The pharmacological blockade of CCR4 seems beneficial because of its pain-relieving effects and its influence on opioid efficacy. The possibilities of using the CCL2/CCL17/CCL22/CCR4 axis as a target in new therapies for many diseases are also discussed.
Integrated Transcriptome and Metabolome Analysis Reveals Phenylpropanoid Biosynthesis and Phytohormone Signaling Contribute to “Candidatus Liberibacter asiaticus” Accumulation in Citrus Fruit Piths (Fluffy Albedo)
Authors: Cui Xiaoqing , Zhan Xuanlin , Liu Yangyang , Huang Zhenhui , Deng Xiaoling , Zheng Zheng , Xu Meirong
Published: December 2022

“Candidatus Liberibacter asiaticus” (CLas) is a phloem-restricted α-proteobacterium that is associated with citrus huanglongbing (HLB), which is the most destructive disease that affects all varieties of citrus. Although midrib is usually used as a material for CLas detection, we recently found that the bacterium was enriched in fruits, especially in the fruit pith. However, no study has revealed the molecular basis of these two parts in responding to CLas infection. Therefore, we performed transcriptome and UHPLC–MS-based targeted and untargeted metabolomics analyses in order to organize the essential genes and metabolites that are involved. Transcriptome and metabolome characterized 4834 differentially expressed genes (DEGs) and 383 differentially accumulated metabolites (DAMs) between the two materials, wherein 179 DEGs and 44 DAMs were affected by HLB in both of the tissues, involving the pathways of phenylpropanoid biosynthesis, phytohormone signaling transduction, starch and sucrose metabolism, and photosynthesis. Notably, we discovered that the gene expression that is related to beta-glucosidase and endoglucanase was up-regulated in fruits. In addition, defense-related gene expression and metabolite accumulation were significantly down-regulated in infected fruits. Taken together, the decreased amount of jasmonic acid, coupled with the reduced accumulation of phenylpropanoid and the increased proliferation of indole-3-acetic acid, salicylic acid, and abscisic acid, compared to leaf midribs, may contribute largely to the enrichment of CLas in fruit piths, resulting in disorders of photosynthesis and starch and sucrose metabolism.
Inhibition of E. coli RecQ Helicase Activity by Structurally Distinct DNA Lesions: Structure—Function Relationships
Authors: Sales Ana H. , Zheng Vincent , Kenawy Maya A. , Kakembo Mark , Zhang Lu , Shafirovich Vladimir , Broyde Suse , Geacintov Nicholas E.
Published: December 2022

DNA helicase unwinding activity can be inhibited by small molecules and by covalently bound DNA lesions. Little is known about the relationships between the structural features of DNA lesions and their impact on unwinding rates and processivities. Employing E.coli RecQ helicase as a model system, and various conformationally defined DNA lesions, the unwinding rate constants kobs = kU + kD, and processivities P = (kU/(kU + kD) were determined (kU, unwinding rate constant; kD, helicase-DNA dissociation rate constant). The highest kobs values were observed in the case of intercalated benzo[a]pyrene (BP)-derived adenine adducts, while kobs values of guanine adducts with minor groove or base-displaced intercalated adduct conformations were ~10–20 times smaller. Full unwinding was observed in each case with the processivity P = 1.0 (100% unwinding). The kobs values of the non-bulky lesions T(6−4)T, CPD cyclobutane thymine dimers, and a guanine oxidation product, spiroiminodihydantoin (Sp), are up to 20 times greater than some of the bulky adduct values; their unwinding efficiencies are strongly inhibited with processivities P = 0.11 (CPD), 0.062 (T(6−4)T), and 0.63 (Sp). These latter observations can be accounted for by correlated decreases in unwinding rate constants and enhancements in the helicase DNA complex dissociation rate constants.
Chlorine Dioxide: Friend or Foe for Cell Biomolecules? A Chemical Approach
Authors: Andrés Celia María Curieses , Lastra José Manuel Pérez de la , Andrés Juan Celia , Plou Francisco J. , Pérez-Lebeña Eduardo
Published: December 2022

This review examines the role of chlorine dioxide (ClO2) on inorganic compounds and cell biomolecules. As a disinfectant also present in drinking water, ClO2 helps to destroy bacteria, viruses, and some parasites. The Environmental Protection Agency EPA regulates the maximum concentration of chlorine dioxide in drinking water to be no more than 0.8 ppm. In any case, human consumption must be strictly regulated since, given its highly reactive nature, it can react with and oxidize many of the inorganic compounds found in natural waters. Simultaneously, chlorine dioxide reacts with natural organic matter in water, including humic and fulvic acids, forming oxidized organic compounds such as aldehydes and carboxylic acids, and rapidly oxidizes phenolic compounds, amines, amino acids, peptides, and proteins, as well as the nicotinamide adenine dinucleotide NADH, responsible for electron and proton exchange and energy production in all cells. The influence of ClO2 on biomolecules is derived from its interference with redox processes, modifying the electrochemical balances in mitochondrial and cell membranes. This discourages its use on an individual basis and without specialized monitoring by health professionals.
A Predictive Pharmacokinetic Model for Immune Cell-Mediated Uptake and Retention of Nanoparticles in Tumors
Authors: Sousa-Junior Ailton , Yang Chun-Ting , Korangath Preethi , Ivkov Robert , Bakuzis Andris
Published: December 2022

A promise of cancer nanomedicine is the “targeted” delivery of therapeutic agents to tumors by the rational design of nanostructured materials. During the past several decades, a realization that in vitro and in vivo preclinical data are unreliable predictors of successful clinical translation has motivated a reexamination of this approach. Mathematical models of drug pharmacokinetics (PK) and biodistribution (BD) are essential tools for small-molecule drugs development. A key assumption underlying these models is that drug-target binding kinetics dominate blood clearance, hence recognition by host innate immune cells is not explicitly included. Nanoparticles circulating in the blood are conspicuous to phagocytes, and inevitable interactions typically trigger active biological responses to sequester and remove them from circulation. Our recent findings suggest that, instead of referring to nanoparticles as designed for active or passive “tumor targeting”, we ought rather to refer to immune cells residing in the tumor microenvironment (TME) as active or passive actors in an essentially “cell-mediated tumor retention” process that competes with active removal by other phagocytes. Indeed, following intravenous injection, nanoparticles induce changes in the immune compartment of the TME because of nanoparticle uptake, irrespective of the nature of tumor targeting moieties. In this study, we propose a 6-compartment PK model as an initial mathematical framework for modeling this tumor-associated immune cell-mediated retention. Published in vivo PK and BD results obtained with bionized nanoferrite® (BNF®) nanoparticles were combined with results from in vitro internalization experiments with murine macrophages to guide simulations. As a preliminary approximation, we assumed that tumor-associated macrophages (TAMs) are solely responsible for active retention in the TME. We model the TAM approximation by relating in vitro macrophage uptake to an effective macrophage avidity term for the BNF® nanoparticles under consideration.
Plasma and Peritoneal Fluid Fibronectin and Collagen IV Levels as Potential Biomarkers of Endometriosis
Authors: Warzecha Damian , Załęcka Julia , Mańka Grzegorz , Kiecka Mariusz , Lipa Michał , Spaczyński Robert , Piekarski Piotr , Banaszewska Beata , Jakimiuk Artur , Issat Tadeusz , Rokita Wojciech , Młodawski Jakub , Szubert Maria , Sieroszewski Piotr , Raba Grzegorz , Szczupak Kamil , Kluz Tomasz , Kluza Marek , Wielgoś Mirosław , Ołdak Łukasz , Leśniewska Anna , Gorodkiewicz Ewa , Laudański Piotr
Published: December 2022

Laparoscopy as a diagnostic tool for patients with suspected endometriosis is associated with several potentially life-threatening complications. Therefore, it is imperative to identify reliable, non-invasive biomarkers of the disease. The aim of this study was to analyse the concentrations of fibronectin and type IV collagen in peritoneal fluid and plasma to assess their role as potential biomarkers in the diagnosis of endometriosis. Fibronectin and collagen IV protein levels were assessed by surface plasmon resonance imaging (SPRi) biosensors with the usage of monoclonal antibodies. All patients enrolled in the study were referred for laparoscopy for the diagnosis of infertility or chronic pelvic pain (n = 84). The study group included patients with endometriosis confirmed during surgery (n = 49). The concentration of fibronectin in the plasma (329.3 ± 98.5 mg/L) and peritoneal fluid (26.8 ± 11.1 μg/L) in women with endometriosis was significantly higher than in the control group (251.2 ± 84.0 mg/L, 7.0 ± 5.9 μg/L). Fibronectin levels were independent of endometriosis stage (p = 0.874, p = 0.469). No significant differences were observed in collagen IV levels (p = 0.385, p = 0.465). The presence of elevated levels of fibronectin may indicate abnormalities in cell–ECM signalling during the course of endometriosis, and may be a potential biomarker for early detection.
Alterations in Kidney Structures Caused by Age Vary According to Sex and Dehydration Condition
Authors: Cognuck Susana Quirós , Almeida Lucas Ferreira de , Reis Wagner L. , Silva Márcia S. , Almeida-Pereira Gislaine , Zorro Sandra V. , Mecawi André S. , Coimbra Terezila Machado , Elias Lucila L. K. , Antunes-Rodrigues José
Published: December 2022

Aging is a complex biological process, resulting in gradual and progressive decline in structure and function in many organ systems. Our objective is to determine if structural changes produced by aging vary with sex in a stressful situation such as dehydration. The expression of Slc12a3 mRNA in the renal cortex, α-smooth muscle actin (α-SMA), and fibronectin was evaluated in male and female rats, aged 3 and 18 months, submitted and not submitted to water deprivation (WD) for 48 h, respectively. When comparing ages, 18-month-old males showed a lower expression of Slc12a3 mRNA than 3-month-old males, and control and WD 18-month-old male and female rats exhibited a higher expression of α-SMA than the respective 3-month-old rats. Fibronectin was higher in both control and WD 18-month-old males than the respective 3-month-old males. In females, only the control 18-month-old rats showed higher fibronectin than the control 3-month-old rats. When we compared sex, control and WD 3-month-old female rats had a lower expression of Slc12a3 mRNA than the respective males. The WD 18-month-old male rats presented a higher expression of fibronectin and α-SMA than the WD 18-month-old female rats. When we compared hydric conditions, the WD 18-month-old males displayed a lower relative expression of Slc12a3 mRNA and higher α-SMA expression than the control 18-month-old males. Aging, sex, and dehydration lead to alterations in kidney structure.
Targeted Phagocytosis Induction for Cancer Immunotherapy via Bispecific MerTK-Engaging Antibodies
Authors: Carrara Stefania C. , Bogen Jan P. , Fiebig David , Grzeschik Julius , Hock Björn , Kolmar Harald
Published: December 2022

The Tyro, Axl, and MerTK receptors (TAMRs) play a significant role in the clearance of apoptotic cells. In this work, the spotlight was set on MerTK, as it is one of the prominent TAMRs expressed on the surface of macrophages and dendritic cells. MerTK-specific antibodies were previously isolated from a transgenic rat-derived immune library with suitable biophysical properties. Further characterisation resulted in an agonistic MerTK antibody that led to phospho AKT activation in a dose-dependent manner. In this proof-of-concept study, a MerTK-specific antibody, MerK28, was combined with tandem, biparatopic EGFR-binding VHH camelid antibody domains (7D9G) in different architectures to generate bispecific antibodies with the capacity to bind EGFR and MerTK simultaneously. The bispecific molecules exhibited appropriate binding properties with regard to both targets in their soluble forms as well as to cells, which resulted in the engagement of macrophage-like THP-1 cells with epidermoid carcinoma A431 cells. Furthermore, targeted phagocytosis in co-culture experiments was observed only with the bispecific variants and not the parental MerTK-binding antibody. This work paves the way for the generation of bispecific macrophage-engaging antibodies for targeted phagocytosis harnessing the immune-modulating roles of MerTK in immunotherapy.
Obesity as a Risk Factor for Breast Cancer—The Role of miRNA
Authors: Hanusek Karolina , Karczmarski Jakub , Litwiniuk Anna , Urbańska Katarzyna , Ambrozkiewicz Filip , Kwiatkowski Andrzej , Martyńska Lidia , Domańska Anita , Bik Wojciech , Paziewska Agnieszka
Published: December 2022

Breast cancer (BC) is the most common cancer diagnosed among women in the world, with an ever-increasing incidence rate. Due to the dynamic increase in the occurrence of risk factors, including obesity and related metabolic disorders, the search for new regulatory mechanisms is necessary. This will help a complete understanding of the pathogenesis of breast cancer. The review presents the mechanisms of obesity as a factor that increases the risk of developing breast cancer and that even initiates the cancer process in the female population. The mechanisms presented in the paper relate to the inflammatory process resulting from current or progressive obesity leading to cell metabolism disorders and disturbed hormonal metabolism. All these processes are widely regulated by the action of microRNAs (miRNAs), which may constitute potential biomarkers influencing the pathogenesis of breast cancer and may be a promising target of anti-cancer therapies.
A Protective Role of Phenylalanine Ammonia-Lyase from Astragalus membranaceus against Saline-Alkali Stress
Authors: Fan Lijuan , Shi Gongfa , Yang Juan , Liu Guiling , Niu Zhaoqian , Ye Wangbin , Wu Songquan , Wang Ling , Guan Qingjie
Published: December 2022

Phenylalanine ammonia-lyase (PAL, E.C.4.3.1.5) catalyzes the benzene propane metabolism and is the most extensively studied enzyme of the phenylpropanoid pathway. However, the role of PAL genes in Astragalus membranaceus, a non-model plant showing high capability toward abiotic stress, is less studied. Here, we cloned AmPAL and found that it encodes a protein that resides in the cytoplasmic membrane. The mRNA of AmPAL was strongly induced by NaCl or NaHCO3 treatment, especially in the root. Overexpressing AmPAL in Nicotiana tabacum resulted in higher PAL enzyme activities, lower levels of malondialdehyde (MDA), and better root elongation in the seedlings under stress treatment compared to the control plants. The protective role of AmPAL under saline-alkali stress was also observed in 30-day soil-grown plants, which showed higher levels of superoxide dismutase (SOD), proline, and chlorophyll compared to wild-type N. Tabacum. Collectively, we provide evidence that AmPAL is responsive to multiple abiotic stresses and that manipulating the expression of AmPAL can be used to increase the tolerance to adverse environmental factors in plants.
Synthesis, Structural Characterization and Biological Activity Evaluation of Novel Cu(II) Complexes with 3-(trifluoromethyl)phenylthiourea Derivatives
Authors: Drzewiecka-Antonik Aleksandra , Struga Marta , Głogowska Agnieszka , Augustynowicz-Kopec Ewa , Dobrzyńska Katarzyna , Chrzanowska Alicja , Wolska Anna , Rejmak Paweł , Klepka Marcin T. , Wrzosek Małgorzata , Bielenica Anna
Published: December 2022

Copper complexes with 1,3-disubstituted thiourea derivatives, all containing 3-(trifluoromethyl)phenyl tail and 1-alkyl/halogen-phenyl substituent, were synthesized. The experimental spectroscopic studies and theoretical calculation revealed that two ligands coordinate to Cu(II) in a bidentate fashion via thiocarbonyl S and deprotonated N atoms of thiourea moiety. Such monomers are characteristic of alkylphenylthiourea complexes, whereas the formation of a sandwich-type dimer is observed for halogeno derivatives. For the first time, the structural identifications of CuN2S2-based complexes using experimental and theoretical X-ray absorption near edge structure are demonstrated. The dimeric halogeno derivatives showed higher antimicrobial activity in comparison with alkylphenylthiourea complexes. The Cu(II) complex of 1-(4-chloro-3-nitrophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea was active against 19 strains of methicillin-resistant Staphylococci (MIC = 2 µg/mL). This derivative acted as a dual inhibitor of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. Additionally, complexes of halogenphenylthiourea strongly inhibited the growth of mycobacteria isolated from tuberculosis patients, even fourfold stronger than the reference isoniazid. The complexes exerted weak to moderate antitumor activity (towards SW480, SW620, and PC3) being non-toxic towards normal HaCaT cells.
Protein Interactome Profiling of Stable Molecular Complexes in Biomaterial Lysate
Authors: Mezentsev Yuri , Ershov Pavel , Yablokov Evgeniy , Kaluzhskiy Leonid , Kupriyanov Konstantin , Gnedenko Oksana , Ivanov Alexis
Published: December 2022

Most proteins function as part of various complexes, forming via stable and dynamic protein–protein interactions (PPIs). The profiling of PPIs expands the fundamental knowledge about the structures, functions, and regulation patterns of protein complexes and intracellular molecular machineries. Protein interactomics aims at solving three main tasks: (1) identification of protein partners and parts of complex intracellular structures; (2) analysis of PPIs parameters (affinity, molecular-recognition specificity, kinetic rate constants, and thermodynamic-parameters determination); (3) the study of the functional role of novel PPIs. The purpose of this work is to update the current state and prospects of multi-omics approaches to profiling of proteins involved in the formation of stable complexes. Methodological paradigm includes a development of protein-extraction and -separation techniques from tissues or cellular lysates and subsequent identification of proteins using mass-spectrometry analysis. In addition, some aspects of authors’ experimental platforms, based on high-performance size-exclusion chromatography, procedures of molecular fishing, and protein identification, as well as the possibilities of interactomic taxonomy of each protein, are discussed.
Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle
Authors: Wang Xueqiao , Wei Zhuying , Gu Mingjuan , Zhu Lin , Hai Chao , Di Anqi , Wu Di , Bai Chunling , Su Guanghua , Liu Xuefei , Yang Lei , Li Guangpeng
Published: December 2022

Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn−/−) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn−/− mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn−/− mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn−/− mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription.
Current Insight into the Role of IL-35 and Its Potential Involvement in the Pathogenesis and Therapy of Atopic Dermatitis
Authors: Zysk Weronika , Gleń Jolanta , Trzeciak Magdalena
Published: December 2022

Interleukin 35 (IL-35), a new member of the IL-12 family of heterodimeric cytokines, could induce two different types of regulatory cells including regulatory T and B cells such as IL-35-induced regulatory T cells and IL-10-producing regulatory B cells (IL-10+Bregs), and IL-35-producing regulatory B cells (IL-35+Bregs). These cells appear to play an important role in modulating the immune system in numerous diseases. Several findings suggested that the expression of IL-35 is dysregulated in many autoimmune, inflammatory, and allergic diseases. Due to the functions of IL-35, it seems that this cytokine may act as an efficient therapeutic strategy for numerous conditions including atopic dermatitis (AD). We aimed to provide a comprehensive overview of the role of IL-35 in modulating the immune system. Additionally, we highlight IL-35 as a specific immunological target, discuss its possible involvement in the pathogenesis of AD, and hypothesize that IL-35 may become a novel target for the treatment of AD. However, further studies are required to evaluate this hypothesis.
Heterologous Expression Reveals Ancient Properties of Tei3—A VanS Ortholog from the Teicoplanin Producer Actinoplanes teichomyceticus
Authors: Yushchuk Oleksandr , Zhukrovska Kseniia , Ostash Bohdan , Fedorenko Victor , Marinelli Flavia
Published: December 2022

Glycopeptide antibiotics (GPAs) are among the most clinically successful antimicrobials. GPAs inhibit cell-wall biosynthesis in Gram-positive bacteria via binding to lipid II. Natural GPAs are produced by various actinobacteria. Being themselves Gram-positives, the GPA producers evolved sophisticated mechanisms of self-resistance to avoid suicide during antibiotic production. These self-resistance genes are considered the primary source of GPA resistance genes actually spreading among pathogenic enterococci and staphylococci. The GPA-resistance mechanism in Actinoplanes teichomyceticus—the producer of the last-resort-drug teicoplanin—has been intensively studied in recent years, posing relevant questions about the role of Tei3 sensor histidine kinase. In the current work, the molecular properties of Tei3 were investigated. The setup of a GPA-responsive assay system in the model Streptomyces coelicolor allowed us to demonstrate that Tei3 functions as a non-inducible kinase, conferring high levels of GPA resistance in A. teichomyceticus. The expression of different truncated versions of tei3 in S. coelicolor indicated that both the transmembrane helices of Tei3 are crucial for proper functioning. Finally, a hybrid gene was constructed, coding for a chimera protein combining the Tei3 sensor domain with the kinase domain of VanS, with the latter being the inducible Tei3 ortholog from S. coelicolor. Surprisingly, such a chimera did not respond to teicoplanin, but indeed to the related GPA A40926. Coupling these experimental results with a further in silico analysis, a novel scenario on GPA-resistance and biosynthetic genes co-evolution in A. teichomyceticus was hereby proposed.
Genome-Wide Characterization of Trehalose-6-Phosphate Synthase Gene Family of Brassica napus and Potential Links with Agronomic Traits
Authors: Hu Ming , Xie Meili , Cui Xiaobo , Huang Junyan , Cheng Xiaohui , Liu Lijiang , Liu Shengyi , Tong Chaobo
Published: December 2022

Trehalose and trehalose-6 phosphate played important roles in floral organ development, embryonic development, cell morphogenesis, and signal transduction under abiotic stress. However, little is known about the trehalose-6-phosphate synthase (TPS) gene family in Brassica napus. In this study, in total, 26 TPS genes in B. napus (BnTPS genes) were identified and classified into two groups. In each group, the BnTPS genes showed relatively conserved gene structures. The protein–protein interaction (PPI) network and enrichment analysis indicated that BnTPS genes were involved in the glycolysis/gluconeogenesis, fructose and mannose metabolism, galactose metabolism, pentose phosphate pathway, carbohydrate transmembrane transport, trehalose–phosphatase activity, etc. The expression of BnTPS genes varied greatly across different tissues, while most of the BnTPS genes showed a considerable improvement in expression under different abiotic stresses, indicating that BnTPS genes were significantly responsive to the abiotic treatments. In addition, the association mapping analysis revealed that eight BnTPS genes were potential regulators of particular agronomic traits. Among them, the gene BnTPS23 was significantly associated with the primary flowering time (PFT), full flowering time (FFT1), and final flowering time (FFT2), suggesting that BnTPS genes may play an important role in regulating key agronomic traits in B. napus. In summary, our research provides a better understanding of BnTPS genes, facilitates the breeding of superior B. napus varieties, and paves the way for future functional studies.