bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of Pharmaceutical Importance of 2H-Pyran-2-One Analogues via Computational Approaches
Authors: Shetgaonkar Samata E. , Kollur Shiva Prasad , Pillai Renjith Raveendran , Thangavel Karthick , Armaković Sanja J. , Armaković Stevan , Shivamallu Chandan , Amachawadi Raghavendra G. , Syed Asad , Elgorban Abdallah M. , Bahkali Ali H. , Singh Fateh V
Published: September 2021

Highly functionalized spirocyclic ketals were synthesized through asymmetric oxidative spirocyclization via carbanion-induced ring transformation of 2H-pyran-2-ones with 1,4-cyclohexandione monoethyleneketal under alkaline conditions. Further acidic-hydrolysis of obtained spirocyclic ketals yields highly substituted 2-tetralone in good yield. Computational analysis based on the DFT calculations and MD simulations has been performed in order to predict and understand global and local reactivity properties of newly synthesized derivatives. DFT calculations covered fundamental reactivity descriptors such as molecular electrostatic potential and average local ionization energies. Nitrogen atom and benzene rings have been recognized as the most important molecular sites from these aspects. Additionally, to predict whether studied compounds are stable towards the autoxidation mechanism, we have also studied the bond dissociation energies for hydrogen abstraction and identified the derivative which might form potentially genotoxic impurities. Interactions with water, including both global and local aspects, have been covered thanks to the MD simulations and calculations of interaction energies with water, counting of formed hydrogen interactions, and radial distribution functions. MD simulations were also used to identify which excipient could be used together with these compounds, and it has been established that the polyvinylpyrrolidone polymer could be highly compatible with these compounds, from the aspect of calculated solubility parameters.
Soil Arching of Piled Embankment in Equal Settlement Pattern: A Discrete Element Analysis
Authors: Wang Kangyu , Cao Jun , Wang Xinquan , Ning Yingjie
Published: September 2021

Soil arching, which occurs in the piled embankments, plays an important role in stress redistribution between the relatively soft subsoil and the stiffer piles. The formation of the soil arching depends on the differential settlement of the embankment fill above the pile and the subsoil. The soil arching effect is barely investigated in the literature from the perspective of differential settlement of piles and soils. Based on the discrete element method (DEM), this paper develops a classic trapdoor test model to investigate the differential settlement in piled embankment during the downward movement of the trapdoor, and to explore the formation mechanism of soil arching in equal settlement pattern by changing the width of the pile cap and the height of the embankment. Due to symmetry, only one section of the laboratory test model is simulated herein. It was found that the soil arching formed under the equal settlement pattern remained unchanged after a certain degree of development, and the height of the equal settlement did not change at 0.7(s-a), where s is the pile spacing, and a is the width of the pile cap. The height of the embankment (H) and the width of the pile cap (a) have a significant influence on the formation of the equal settlement pattern when the width of the trapdoor is kept constant. Both the decrease in “H” and the increase in “a” facilitate the differential settlement of the soil between the piles and the pile-soil, enabling the slip surface to develop upward gradually, thereby hindering the formation of the equal settlement pattern.
Comprehensive Study of Li+/Ni2+ Disorder in Ni-Rich NMCs Cathodes for Li-Ion Batteries
Authors: Orlova Elena D. , Savina Aleksandra A. , Abakumov Sergey A. , Morozov Anatolii V. , Abakumov Artem M.
Published: September 2021

The layered oxides LiNixMnyCozO2 (NMCs, x + y + z = 1) with high nickel content (x ≥ 0.6, Ni-rich NMCs) are promising high-energy density-positive electrode materials for Li-ion batteries. Their electrochemical properties depend on Li+/Ni2+ cation disordering originating from the proximity of the Li+ and Ni2+ ionic radii. We synthesized a series of the LiNi0.8Mn0.1Co0.1O2 NMC811 adopting two different disordering schemes: Ni for Li substitution at the Li site in the samples finally annealed in air, and close to Ni↔Li antisite disorder in the oxygen-annealed samples. The defect formation scenario was revealed with Rietveld refinement from powder X-ray diffraction data, and then the reliability of semi-quantitative parameters, such as I003/I104 integral intensity ratio and c/(2√6a) ratio of pseudocubic subcell parameters, was verified against the refined defect concentrations. The I003/I104 ratio can serve as a quantitative measure of g(NiLi) only after explicit correction of intensities for preferred orientation. Being normalized by the total scattering power of the unit cell, the I003/I104 ratio depends linearly on g(NiLi) for each disordering scheme. The c/(2√6a) ratio appears to be not reliable and cannot be used for a quantitative estimate of g(NiLi). In turn, the volume of the R3¯m unit cell correlates linearly with g(NiLi), at least for defect concentrations not exceeding 5%. The microscopy techniques such as high-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and electron diffraction tomography (EDT) allow us to study the materials locally, still, there is no proper quantitative approach for comprehensive analysis of defects. In the present work, the TEM-assisted quantitative Li+/Ni2+ disordering analysis with EDT and HAADF-STEM in six Ni-rich NMC samples with various defects content is demonstrated. Noteworthy, while PXRD and EDT methods demonstrate overall defect amounts, HAADF-STEM allows us to quantitatively distinguish regions with various disordering extents. Therefore, the combination of mentioned PXRD and TEM methods gives the full picture of Li+/Ni2+ mixing defects in Ni-rich NMCs.
The Structural Performance of CFRP Composite Plates Assembled with Fiber Bragg Grating Sensors
Authors: Wang Hua-Ping , Chen Hao , Chen Cong , Zhang Hu-Yuan , Jiang Hao , Song Tao , Feng Si-Yuan
Published: September 2021

Carbon fiber reinforced polymer (CFRP) composites have been extensively used in airframes, train bodies, and engine blades for their properties of high strength, low weight, and good stability. The in-service structural performance of CFRP composites is always an important point to be investigated for its influence on structural safety. For this reason, CFRP composite plates assembled with fiber Bragg grating (FBG) sensors were developed, and the in-service structural characteristics of the CFRP plates were interpreted by FBG signals measured through time. A theoretical analysis supported by a numerical method has been provided. Experimental testing was conducted to check the proposed sensing technique for the dynamic response identification of the CFRP plate. The curing process of the bilayer CFRP plated inserted with FBGs in series was also explored. The results showed that the surface-attached FBGs in series could accurately characterize the dynamic response of the CFRP plate, and a good agreement between the numerical and testing results was observed. The strain and temperature distributions during the curing process of the bilayer plate indicated that the in-service structural performance of bilayer CFRP plates can be configured by the assembled FBG sensors. This study can support the structural health monitoring of projects by using CFRP composites.
Density Functional Theory Study of Substitution Effects on the Second-Order Nonlinear Optical Properties of Lindquist-Type Organo-Imido Polyoxometalates
Authors: Rtibi Emna , Champagne Benoit
Published: September 2021

Density functional theory and time-dependent density functional theory have been enacted to investigate the effects of donor and acceptor on the first hyperpolarizability of Lindquist-type organo-imido polyoxometalates (POMs). These calculations employ a range-separated hybrid exchange-correlation functional (ωB97X-D), account for solvent effects using the implicit polarizable continuum model, and analyze the first hyperpolarizabilities by using the two-state approximation. They highlight the beneficial role of strong donors as well as of π-conjugated spacers (CH=CH rather than C≡C) on the first hyperpolarizabilities. Analysis based on the unit sphere representation confirms the one-dimensional push-pull π-conjugated character of the POMs substituted by donor groups and the corresponding value of the depolarization ratios close to 5. Furthermore, the use of the two-state approximation is demonstrated to be suitable for explaining the origin of the variations of the first hyperpolarizabilities as a function of the characteristics of a unique low-energy charge-transfer excited state and to attribute most of the first hyperpolarizability changes to the difference of dipole moment between the ground and that charge-transfer excited state.
Preference for Facial Symmetry Depends on Study Design
Authors: Lee Anthony J. , De La Mare Jessica K. , Moore Hannah R. , Umeh Pamela C.
Published: September 2021

Facial symmetry is purportedly attractive, though methods for measuring preference for facial symmetry vary between studies. Some studies have used a two-alternative forced choice (2AFC) task, while others have used a ratings task. How researchers manipulate facial symmetry also varies; some studies have used faces manipulated to be more (or perfectly) symmetrical, while others have used faces manipulated to be more asymmetrical. Here, across three studies, we evaluate and compare these different methods. In Studies 1 and 2 (N = 340 and 256, respectively), we compare facial symmetry preferences as measured by the 2AFC and ratings tasks. Across both studies, we consistently found a significant preference for facial symmetry when using the 2AFC task, but not with the ratings task. Additionally, correlations between facial symmetry preferences as measured by the two tasks were weak or showed no association. In Study 3, 159 participants rated the attractiveness of faces manipulated to be either symmetrical or more asymmetrical. The asymmetrical faces were rated as significantly less attractive compared to the original faces, while the difference in attractiveness ratings between the original and symmetrical versions was comparatively much smaller. These studies suggest that preference for facial symmetry depends greatly on the study design.
Scale Symmetry and Friction
Authors: Sloan David
Published: September 2021

Dynamical similarities are non-standard symmetries found in a wide range of physical systems that identify solutions related by a change of scale. In this paper, we will show through a series of examples how this symmetry extends to the space of couplings, as measured through observations of a system. This can be exploited to focus on observations that can be used to distinguish between different theories and identify those which give rise to identical physical evolutions. These can be reduced into a description that makes no reference to scale. The resultant systems can be derived from Herglotz’s principle and generally exhibit friction. Here, we will demonstrate this through three example systems: the Kepler problem, the N-body system and Friedmann–Lemaître–Robertson–Walker cosmology.
ETHERST: Ethereum-Based Public Key Infrastructure Identity Management with a Reward-and-Punishment Mechanism
Authors: Koa Chong-Gee , Heng Swee-Huay , Chin Ji-Jian
Published: September 2021

Public Key Infrastructure (PKI) is the fundamental of secure digital communications. It provides a secure means to authenticate identities over the Internet. Symmetric or asymmetric encryption schemes are widely used in identity authentication in any kind of PKI. The conventional PKI has several drawbacks due to the centralized and non-transparent design. Several recent research works utilize blockchain technology to overcome the limitations of conventional implementations of PKI. Blockchain-based PKI integrates blockchain technology with PKI to form a new type of decentralized PKI (DPKI). Several works utilize the currency property in blockchains to implement the reward-and-punishment mechanism. In this paper, we propose a smart contract-based PKI which utilizes the Ethereum smart contract to build a new type of blockchain-based PKI with the reward-and-punishment mechanism using ERC-20 tokens. It has several advantages over previous implementations of similar research that use Ethereum’s main currency—Ether.
Polyazulene-Based Materials for Heavy Metal Ion Detection. 3. (E)-5-((6-t-Butyl-4,8-dimethylazulen-1-yl) diazenyl)-1H-tetrazole-Based Modified Electrodes
Authors: Enache Laura-Bianca , Anăstăsoaie Veronica , Lete Cecilia , Brotea Alina Giorgiana , Matica Ovidiu-Teodor , Amarandei Cristina-Andreea , Brandel Jérémy , Ungureanu Eleonora-Mihaela , Enăchescu Marius
Published: September 2021

A recently synthesized azulene-tetrazole molecular receptor is proposed in this paper to continue the series of azulene substituted compounds that have been developed to build polyazulene-based materials for heavy metal (HM) ion detection. This study focuses on characterization of (E)-5-((6-t-butyl-4,8-dimethylazulen-1-yl) diazenyl)-1H-tetrazole (L) by electrochemical techniques in view of its use for designing electrochemical sensors for HM ion complexation. The character of redox processes was proved by cyclic, differential pulse, and rotating disk electrode voltammetry. An in-depth thermodynamic study of the complexation properties of the free ligand with Pb(II) and Cd(II) from aqueous solutions was performed, and the stoichiometry and stability constant values were determined. Chemically modified electrodes (CMEs) based on L (L-CMEs) prepared by controlled potential electrolysis (CPE) at different applied potentials and charges were characterized by cyclic voltammetry and electrochemical impedance spectroscopy (EIS). Their surface morphology was examined by scanning electron microscopy (SEM). The complexing properties of L-CMEs were investigated towards the detection of HM ions by anodic stripping and compared to the stability constants of the complexes in solution. Voltametric curves showed well-defined peaks for Pb (II), Cd (II), Cu (II) and Hg (II), but the responses differ from each other and vary depending on the ion concentrations in the accumulation solutions. The best results were obtained for Pb(II) and Cd(II) ions. The results obtained for Pb(II) are promising and can be used for its analysis in water solutions (detection limit of about 10−9 M).
Laboratory Investigation of Hydraulic Parameters on Inclined Drop Equipped with Fishway Elements
Authors: Daneshfaraz Rasoul , Aminvash Ehsan , Bagherzadeh Mohammad , Ghaderi Amir , Kuriqi Alban , Najibi Amir , Ricardo Ana M.
Published: September 2021

This study aims to provide a way to increase the energy dissipation of flow in the inclined drop with environmental and economic considerations. Eighty-one experiments were performed on three types of simple inclined drop and inclined drop equipped with hole and without hole fishway elements with a 200~600 L/min flow rate. In this study, the effect of using fishway elements on hydraulic parameters regarding flow pattern, energy dissipation, relative downstream depth, relative aeration length, relative length of the hydraulic jump, and downstream Froude number of an inclined drop was investigated through physical modeling following the symmetry law. The results showed that in all experimental models, with increasing the relative critical depth parameter, the energy dissipation values increase, and the downstream Froude number decreases. The parameters of relative downstream depth, relative length of a hydraulic jump, and relative aeration length also increase with increasing relative critical depth. On average, 88% of the flow energy dissipation increases with the design of the fishway elements on the structure compared to the simple drop. Model M7 (with holes fish elements) shows the highest energy dissipation, and Model M2 (without holes fish elements) has the highest flow aeration length and relative downstream water depth.
Causal Loop Diagramming of Socioeconomic Impacts of COVID-19: State-of-the-Art, Gaps and Good Practices
Authors: Strelkovskii Nikita , Rovenskaya Elena
Published: September 2021

The complexity, multidimensionality, and persistence of the COVID-19 pandemic have prompted both researchers and policymakers to turn to transdisciplinary methods in dealing with the wickedness of the crisis. While there are increasing calls to use systems thinking to address the intricacy of COVID-19, examples of practical applications of systems thinking are still scarce. We revealed and reviewed eight studies which developed causal loop diagrams (CLDs) to assess the impact of the COVID-19 pandemic on a broader socioeconomic system. We find that major drivers across all studies are the magnitude of the infection spread and government interventions to curb the pandemic, while the most impacted variables are public perception of the pandemic and the risk of infection. The reviewed COVID-19 CLDs consistently exhibit certain complexity patterns, for example, they contain a higher number of two- and three-element feedback loops than comparable random networks. However, they fall short in representing linear complexity such as multiple causes and effects, as well as cascading impacts. We also discuss good practices for creating and presenting CLDs using the reviewed diagrams as illustration. We suggest that increasing transparency and rigor of the CLD development processes can help to overcome the lack of systems thinking applications to address the challenges of the COVID-19 crisis.
Design, Construction and Tests of a Low-Cost Myoelectric Thumb
Authors: Ayvali Murat , Wickenkamp Inge , Ehrmann Andrea
Published: September 2021

Myoelectric signals can be used to control prostheses or exoskeletons as well as robots, i.e., devices assisting the user or replacing a missing part of the body. A typical application of myoelectric prostheses is the human hand. Here, the development of a low-cost myoelectric thumb is described, which can either be used as an additional finger or as prosthesis. Combining 3D printing with inexpensive sensors, electrodes, and electronics, the recent project offers the possibility to produce an individualized myoelectric thumb at significantly lower costs than commercial myoelectric prostheses. Alternatively, a second thumb may be supportive for people with special manual tasks. These possibilities are discussed together with disadvantages of a second thumb and drawbacks of the low-cost solution in terms of mechanical properties and wearing comfort. The study shows that a low-cost customized myoelectric thumb can be produced in this way, but further research on controlling the thumb as well as improving motorization are necessarily to make it fully usable for daily tasks.
Early Warning of Resistance to Bt Toxin Vip3Aa in Helicoverpa zea
Authors: Yang Fei , Kerns David L. , Little Nathan S. , Santiago González José C. , Tabashnik Bruce E.
Published: September 2021

Evolution of resistance by pests can reduce the benefits of crops genetically engineered to produce insecticidal proteins from Bacillus thuringiensis (Bt). Because of the widespread resistance of Helicoverpa zea to crystalline (Cry) Bt toxins in the United States, the vegetative insecticidal protein Vip3Aa is the only Bt toxin produced by Bt corn and cotton that remains effective against some populations of this polyphagous lepidopteran pest. Here we evaluated H. zea resistance to Vip3Aa using diet bioassays to test 42,218 larvae from three lab strains and 71 strains derived from the field during 2016 to 2020 in Arkansas, Louisiana, Mississippi, Tennessee, and Texas. Relative to the least susceptible of the three lab strains tested (BZ), susceptibility to Vip3Aa of the field-derived strains decreased significantly from 2016 to 2020. Relative to another lab strain (TM), 7 of 16 strains derived from the field in 2019 were significantly resistant to Vip3Aa, with up to 13-fold resistance. Susceptibility to Vip3Aa was significantly lower for strains derived from Vip3Aa plants than non-Vip3Aa plants, providing direct evidence of resistance evolving in response to selection by Vip3Aa plants in the field. Together with previously reported data, the results here convey an early warning of field-evolved resistance to Vip3Aa in H. zea that supports calls for urgent action to preserve the efficacy of this toxin.
Analysis of the Necrosis-Inducing Components of the Venom of Naja atra and Assessment of the Neutralization Ability of Freeze-Dried Antivenom
Authors: Ho Cheng-Hsuan , Chiang Liao-Chun , Mao Yan-Chiao , Lan Kuo-Cheng , Tsai Shih-Hung , Shih Yu-Jen , Tzeng Yuan-Sheng , Lin Chin-Sheng , Lin Wen-Loung , Fang Wei-Hsuan , Chen Kuang-Ting , Lee Chi-Hsin , Chiang Dapi Meng-Lin , Liu Shing-Hwa
Published: September 2021

Patients bitten by Naja atra who are treated with bivalent freeze-dried neurotoxic antivenom in Taiwan have an improved survival rate but develop necrotic wound changes. The World Health Organization (WHO) has suggested using the minimum necrotizing dose (MND) of venom as a method of evaluating the neutralization effect of antivenom. The aim of this study was to evaluate the effectiveness of antivenom for the prevention of necrosis based on the MND and clarify which component of the venom of N. atra induces necrosis. The neurotoxins (NTXs) were removed from the crude venom (deNTXs), and different concentrations of deNTXs were injected intradermally into the dorsal skin of mice. After three days, the necrotic lesion diameter was found to be approximately 5 mm, and the MND was calculated. A reduction in the necrotic diameter of 50% was used to identify the MND50. Furthermore, both phospholipase A2 (PLA2) and cytotoxins (CTXs) were separately removed from the deNTXs to identify the major necrosis-inducing factor, and the necrotic lesions were scored. All mice injected with deNTXs survived for three days and developed necrotic wounds. The MND of the deNTXs for mice was 0.494 ± 0.029 µg/g, that of the deNTXs-dePLA2 (major component retained: CTXs) was 0.294 ± 0.05 µg/g, and that of the deNTX-deCTX (major component retained: PLA2) venom was greater than 1.25 µg/g. These values show that CTX is the major factor inducing necrosis. These results suggest that the use of the deNTXs is necessary to enable the mice to survive long enough to develop venom-induced cytolytic effects. CTXs play a major role in N. atra-related necrosis. However, the MND50 could not be identified in this study, which meant that the antivenom did not neutralize venom-induced necrosis.
Finding Species-Specific Extracellular Surface-Facing Proteomes in Toxic Dinoflagellates
Authors: Chan Kenrick Kai-yuen , Kong Hang-kin , Tse Sirius Pui-kam , Chan Zoe , Lo Pak-yeung , Kwok Kevin W. H. , Lo Samuel Chun-lap
Published: September 2021

As a sequel to our previous report of the existence of species-specific protein/peptide expression profiles (PEPs) acquired by mass spectrometry in some dinoflagellates, we established, with the help of a plasma-membrane-impermeable labeling agent, a surface amphiesmal protein extraction method (SAPE) to label and capture species-specific surface proteins (SSSPs) as well as saxitoxins-producing-species-specific surface proteins (Stx-SSPs) that face the extracellular space (i.e., SSSPsEf and Stx-SSPsEf). Five selected toxic dinoflagellates, Alexandrium minutum, A. lusitanicum, A. tamarense, Gymnodinium catenatum, and Karenia mikimotoi, were used in this study. Transcriptomic databases of these five species were also constructed. With the aid of liquid chromatography linked-tandem mass spectrometry (LC-MS/MS) and the transcriptomic databases of these species, extracellularly facing membrane proteomes of the five different species were identified. Within these proteomes, 16 extracellular-facing and functionally significant transport proteins were found. Furthermore, 10 SSSPs and 6 Stx-SSPs were identified as amphiesmal proteins but not facing outward to the extracellular environment. We also found SSSPsEf and Stx-SSPsEf in the proteomes. The potential functional correlation of these proteins towards the production of saxitoxins in dinoflagellates and the degree of species specificity were discussed accordingly.
The Influence of Zearalenone on Selected Hemostatic Parameters in Sexually Immature Gilts
Authors: Jakimiuk Ewa , Radwińska Justyna , Woźny Maciej , Pomianowski Andrzej , Brzuzan Paweł , Wojtacha Paweł , Obremski Kazimierz , Zielonka Łukasz
Published: September 2021

Vascular toxicity induced by xenobiotics is associated with dysfunctions or damage to endothelial cells, changes in vascular permeability or dysregulation of the vascular redox state. The aim of this study was to determine whether per os administration of zearalenone (ZEN) influences selected hemostatic parameters in prepubertal gilts. This study was performed on female gilts divided into a control group which received placebo and an experimental group which received ZEN at a dose of 5.0 µg·kg−1 b.w. × day−1. On days 14, 28 and 42, blood samples were collected from the animals for analyses of hematological, coagulation and fibrinolysis parameters, nitric oxide, von Willebrand factor antigen content and catalase activity. The results demonstrated that the treatment of gilts with ZEN at a dose below no observable adverse effect level did not affect the primary hemostasis and the blood coagulation cascade. However, ZEN could have temporarily affected the selected indicators of endothelial cell function (increase of von Willebrand factor, decrease of nitric oxide levels) and the oxidative status plasma (decrease of catalase activity) of the exposed gilts. In summary, these results suggest that the adaptive response to ZEN-exposure can induce a transient imbalance in the vascular system by acting on vascular endothelial cells.
Geographical Information System (GIS) Based Multi-Criteria Decision Analysis for Categorization of the Villages: In the Case of Kabul New City Villages
Authors: Habibi Said Mustafa , Ono Hiroko , Shukla Ashutosh
Published: September 2021

Kabul is experiencing the most powerful wave of urbanization in its history. With the rapid increase of population, typical urban problems such as lowering of the groundwater table, an influx of returnees, traffic jams, deterioration of sanitation, etc., are becoming critical. In 2006, to decrease the pressure from existing Kabul and take measurements for future urbanization process, an independent board was established for the development of a new city adjacent to the existing Kabul by the name of Kabul New City (KNC). There were already 54 villages that existed there. Due to smoothly implementing the master plan and supporting the existing villages, it was necessary to prepare village development plans. As each village has its own characteristics from the urban planning perspective, therefore this research explains a method for categorization of villages through multi-criteria decision analysis; seven potential criteria were identified and rated in collaboration with experts, and Super Decision software was used as an Analytic Hierarchy Process (AHP) tool to weight the criteria. The final output is a map showing different categories of villages. It will assist the government and urban planners in choosing a clear strategy and platform for developing each individual village to be sustainable and applicable.
Meat Exudate for Detection of African Swine Fever Virus Genomic Material and Anti-ASFV Antibodies
Authors: Onyilagha Chukwunonso , Nash Mikyla , Perez Orlando , Goolia Melissa , Clavijo Alfonso , Richt Juergen A. , Ambagala Aruna
Published: September 2021

African swine fever (ASF) is one of the most important viral diseases of pigs caused by the ASF virus (ASFV). The virus is highly stable over a wide range of temperatures and pH and can survive in meat and meat products for several months, leading to long-distance transmission of ASF. Whole blood, serum, and organs from infected pigs are used routinely as approved sample types in the laboratory diagnosis of ASF. However, these sample types may not always be available. Here, we investigated meat exudate as an alternative sample type for the detection of ASFV-specific nucleic acids and antibodies. Pigs were infected with various ASFV strains: the highly virulent ASFV Malawi LIL 18/2 strain, the moderately-virulent ASFV Estonia 2014 strain, or the low-virulent ASFV OURT/88/3 strain. The animals were euthanized on different days post-infection (dpi), and meat exudates were collected and tested for the presence of ASFV-specific nucleic acids and antibodies. Animals infected with the ASFV Malawi LIL 18/2 developed severe clinical signs and succumbed to the infection within seven dpi, while pigs infected with ASFV Estonia 2014 also developed clinical signs but survived longer, with a few animals seroconverting before succumbing to the ASFV infection or being euthanized as they reached humane endpoints. Pigs infected with ASFV OURT/88/3 developed transient fever and seroconverted without mortality. ASFV genomic material was detected in meat exudate from pigs infected with ASFV Malawi LIL 18/2 and ASFV Estonia 2014 at the onset of viremia but at a lower amount when compared to the corresponding whole blood samples. Low levels of ASFV genomic material were detected in the whole blood of ASFV OURT/88/3-infected pigs, and no ASFV genomic material was detected in the meat exudate of these animals. Anti-ASFV antibodies were detected in the serum and meat exudate derived from ASFV OURT/88/3-infected pigs and in some of the samples derived from the ASFV Estonia 2014-infected pigs. These results indicate that ASFV genomic material and anti-ASFV antibodies can be detected in meat exudate, indicating that this sample can be used as an alternative sample type for ASF surveillance when routine sample types are unavailable or are not easily accessible.
Serological Surveillance of Influenza D Virus in Ruminants and Swine in West and East Africa, 2017–2020
Authors: Sanogo Idrissa Nonmon , Kouakou Casimir , Batawui Komla , Djegui Fidélia , Byarugaba Denis K. , Adjin Rachidatou , Adjabli Komlan , Wabwire-Mangen Fred , Erima Bernard , Atim Gladys , Ukuli Qouilazoni A. , Tugume Titus , Dogno Koffi , Go-Maro Wolali , Couacy-Hymann Emmanuel , Kayali Ghazi , McKenzie Pamela , Webby Richard J. , Ducatez Mariette F.
Published: September 2021

Influenza D virus (IDV) was first isolated in 2011 in Oklahoma, USA from pigs presenting with influenza-like symptoms. IDV is known to mainly circulate in ruminants, especially cattle. In Africa, there is limited information on the epidemiology of IDV, although the virus has likely circulated in the region since 2012. In the present study, we investigated the seropositivity of IDV among domestic ruminants and swine in West and East Africa from 2017 to 2020. Serum samples were analyzed using the hemagglutination inhibition (HI) assay. Our study demonstrated that IDV is still circulating in Africa, with variations in seropositivity among countries and species. The highest seropositivity was detected in cattle (3.9 to 20.9%). Our data highlights a need for extensive surveillance of IDV in Africa in order to better understand the epidemiology of the virus in the region.
Bacteriophages M13 and T4 Increase the Expression of Anchorage-Dependent Survival Pathway Genes and Down Regulate Androgen Receptor Expression in LNCaP Prostate Cell Line
Authors: Sanmukh Swapnil Ganesh , dos Santos Nilton José , Barquilha Caroline Nascimento , Cucielo Maira Smaniotto , de Carvalho Márcio , dos Reis Patricia Pintor , Delella Flávia Karina , Carvalho Hernandes F. , Felisbino Sérgio Luis
Published: September 2021

Wild-type or engineered bacteriophages have been reported as therapeutic agents in the treatment of several types of diseases, including cancer. They might be used either as naked phages or as carriers of antitumor molecules. Here, we evaluate the role of bacteriophages M13 and T4 in modulating the expression of genes related to cell adhesion, growth, and survival in the androgen-responsive LNCaP prostatic adenocarcinoma-derived epithelial cell line. LNCaP cells were exposed to either bacteriophage M13 or T4 at a concentration of 1 × 105 pfu/mL, 1 × 106 pfu/mL, and 1 × 107 pfu/mL for 24, 48, and 72 h. After exposure, cells were processed for general morphology, cell viability assay, and gene expression analyses. Neither M13 nor T4 exposure altered cellular morphology, but both decreased the MTT reduction capacity of LNCaP cells at different times of treatment. In addition, genes AKT, ITGA5, ITGB1, ITGB3, ITGB5, MAPK3, and PI3K were significantly up-regulated, whilst the genes AR, HSPB1, ITGAV, and PGC1A were down-regulated. Our results show that bacteriophage M13 and T4 interact with LNCaP cells and effectively promote gene expression changes related to anchorage-dependent survival and androgen signaling. In conclusion, phage therapy may increase the response of PCa treatment with PI3K/AKT pathway inhibitors.
Identification of Potential Drug Targets of Broad-Spectrum Inhibitors with a Michael Acceptor Moiety Using Shotgun Proteomics
Authors: Chu Hao-Wei , Sethy Bidyadhar , Hsieh Pei-Wen , Horng Jim-Tong
Published: September 2021

The Michael addition reaction is a spontaneous and quick chemical reaction that is widely applied in various fields. This reaction is performed by conjugating an addition of nucleophiles with α, β-unsaturated carbonyl compounds, resulting in the bond formation of C-N, C-S, C-O, and so on. In the development of molecular materials, the Michael addition is not only used to synthesize chemical compounds but is also involved in the mechanism of drug action. Several covalent drugs that bond via Michael addition are regarded as anticarcinogens and anti-inflammatory drugs. Although drug development is mainly focused on pharmaceutical drug discovery, target-based discovery can provide a different perspective for drug usage. However, considerable time and labor are required to define a molecular target through molecular biological experiments. In this review, we systematically examine the chemical structures of current FDA-approved antiviral drugs for potential Michael addition moieties with α, β-unsaturated carbonyl groups, which may exert an unidentified broad-spectrum inhibitory mechanism to target viral or host factors. We thus propose that profiling the targets of antiviral agents, such as Michael addition products, can be achieved by employing a high-throughput LC-MS approach to comprehensively analyze the interaction between drugs and targets, and the subsequent drug responses in the cellular environment to facilitate drug repurposing and/or identify potential adverse effects, with a particular emphasis on the pros and cons of this shotgun proteomic approach.
Enrichment of SARS-CoV-2 Entry Factors and Interacting Intracellular Genes in Tissue and Circulating Immune Cells
Authors: Devaprasad Abhinandan , Pandit Aridaman
Published: September 2021

SARS-CoV-2 uses ACE2 and TMPRSS2 to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV-associated genes, and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We found that in general a small fraction of cells express ACE2 in the different tissues, including nasal, bronchi, and lungs. We show that a small fraction of immune cells (including T cells, macrophages, dendritic cells) found in tissues also express ACE2. We show that healthy circulating immune cells do not express ACE2 and TMPRSS2. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T cells) in the PBMC of COVID-19 patients express ACE2 and TMPRSS2. Additionally, we found that a large spectrum of cells (in tissues and circulation) in both healthy and COVID-19-positive patients were significantly enriched for SARS-CoV-2 factors, such as those associated with RHOA and RAB GTPases, mRNA translation proteins, COPI- and COPII-mediated transport, and integrins. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect tissue and circulating immune cells to better understand the virus’ mechanism of action.
Natural Selection of H5N1 Avian Influenza A Viruses with Increased PA-X and NS1 Shutoff Activity
Authors: Nogales Aitor , Villamayor Laura , Utrilla-Trigo Sergio , Ortego Javier , Martinez-Sobrido Luis , DeDiego Marta L.
Published: September 2021

Influenza A viruses (IAV) can infect a broad range of mammalian and avian species. However, the host innate immune system provides defenses that restrict IAV replication and infection. Likewise, IAV have evolved to develop efficient mechanisms to counteract host antiviral responses to efficiently replicate in their hosts. The IAV PA-X and NS1 non-structural proteins are key virulence factors that modulate innate immune responses and virus pathogenicity during infection. To study the determinants of IAV pathogenicity and their functional co-evolution, we evaluated amino acid differences in the PA-X and NS1 proteins of early (1996–1997) and more recent (since 2016) H5N1 IAV. H5N1 IAV have zoonotic and pandemic potential and represent an important challenge both in poultry farming and human health. The results indicate that amino acid changes occurred over time, affecting the ability of these two non-structural H5N1 IAV proteins to inhibit gene expression and affecting virus pathogenicity. These results highlight the importance to monitor the evolution of these two virulence factors of IAV, which could result in enhanced viral replication and virulence.
DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication
Authors: Abdullah Sahibzada Waheed , Wu Jin’en , Zhang Yun , Bai Manyuan , Guan Junyong , Liu Xiangtao , Sun Shiqi , Guo Huichen
Published: September 2021

In cells, the contributions of DEAD-box helicases (DDXs), without which cellular life is impossible, are of utmost importance. The extremely diverse roles of the nucleolar helicase DDX21, ranging from fundamental cellular processes such as cell growth, ribosome biogenesis, protein translation, protein–protein interaction, mediating and sensing transcription, and gene regulation to viral manipulation, drew our attention. We designed this project to study virus–host interactions and viral pathogenesis. A pulldown assay was used to investigate the association between foot-and-mouth disease virus (FMDV) and DDX21. Further insight into the DDX21–FMDV interaction was obtained through dual-luciferase, knockdown, overexpression, qPCR, and confocal microscopy assays. Our results highlight the antagonistic feature of DDX21 against FMDV, as it progressively inhibited FMDV internal ribosome entry site (IRES) -dependent translation through association with FMDV IRES domains 2, 3, and 4. To subvert this host helicase antagonism, FMDV degraded DDX21 through its non-structural proteins 2B, 2C, and 3C protease (3Cpro). Our results suggest that DDX21 is degraded during 2B and 2C overexpression and FMDV infection through the caspase pathway; however, DDX21 is degraded through the lysosomal pathway during 3Cpro overexpression. Further investigation showed that DDX21 enhanced interferon-beta and interleukin-8 production to restrict viral replication. Together, our results demonstrate that DDX21 is a novel FMDV IRES trans-acting factor, which negatively regulates FMDV IRES-dependent translation and replication.
Treatments for HBV: A Glimpse into the Future
Authors: Bartoli Alessandra , Gabrielli Filippo , Tassi Andrea , Cursaro Carmela , Pinelli Ambra , Andreone Pietro
Published: September 2021

The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.
Zika Virus Non-Structural Protein 1 Antigen-Capture Immunoassay
Authors: Beddingfield Brandon J. , Hartnett Jessica N. , Wilson Russell B. , Kulakosky Peter C. , Andersen Kristian G. , Robles-Sikisaka Refugio , Grubaugh Nathan D. , Aybar Argelia , Nunez Maria-Zunilla , Fermin Cesar D. , Garry Robert F.
Published: September 2021

Infection with Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, typically results in mild self-limited illness, but severe neurological disease occurs in a limited subset of patients. In contrast, serious outcomes commonly occur in pregnancy that affect the developing fetus, including microcephaly and other major birth defects. The genetic similarity of ZIKV to other widespread flaviviruses, such as dengue virus (DENV), presents a challenge to the development of specific ZIKV diagnostic assays. Nonstructural protein 1 (NS1) is established for use in immunodiagnostic assays for flaviviruses. To address the cross-reactivity of ZIKV NS1 with proteins from other flaviviruses we used site-directed mutagenesis to modify putative epitopes. Goat polyclonal antibodies to variant ZIKV NS1 were affinity-purified to remove antibodies binding to the closely related NS1 protein of DENV. An antigen-capture ELISA configured with the affinity-purified polyclonal antibody showed a linear dynamic range between approximately 500 and 30 ng/mL, with a limit of detection of between 1.95 and 7.8 ng/mL. NS1 proteins from DENV, yellow fever virus, St. Louis encephalitis virus and West Nile virus showed significantly reduced reactivity in the ZIKV antigen-capture ELISA. Refinement of approaches similar to those employed here could lead to development of ZIKV-specific immunoassays suitable for use in areas where infections with related flaviviruses are common.
SARS-CoV-2 Delta Variant Pathogenesis and Host Response in Syrian Hamsters
Authors: Mohandas Sreelekshmy , Yadav Pragya Dhruv , Shete Anita , Nyayanit Dimpal , Sapkal Gajanan , Lole Kavita , Gupta Nivedita
Published: September 2021

B.1.617 is becoming a dominant Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) lineage worldwide with many sublineages, of which B.1.617.2 is designated as a variant of concern. The pathogenicity of B.1.617.2 (Delta) and B.1.617.3 lineage of SARS-CoV-2 was evaluated and compared with that of B.1, an early virus isolate with D614G mutation in a Syrian hamster model. Viral load, antibody response, and lung disease were studied. There was no significant difference in the virus shedding pattern among these variants. High levels of SARS-CoV-2 sub genomic RNA were detected in the respiratory tract of hamsters infected with the Delta variant for 14 days, which warrants further transmission studies. The Delta variant induced lung disease of moderate severity in about 40% of infected animals, which supports the attributed disease severity of the variant. Cross neutralizing antibodies were detected in animals infected with B.1, Delta, and B.1.617.3 variant, but neutralizing capacity was significantly lower with B.1.351 (Beta variant).
Inhibition of MAVS Aggregation-Mediated Type-I Interferon Signaling by Foot-and-Mouth Disease Virus VP3
Authors: Ekanayaka Pathum , Lee Byeong-Hoon , Weerawardhana Asela , Chathuranga Kiramage , Park Jong-Hyeon , Lee Jong-Soo
Published: September 2021

As a structural protein of the Foot-and-mouth disease virus (FMDV), VP3 plays a vital role in virus assembly and inhibiting the interferon (IFN) signal transduction to promote FMDV replication. Previous studies demonstrated that FMDV VP3 blocks the type-I IFN response by inhibiting the mRNA expression of the mitochondrial antiviral-signaling protein (MAVS); however, the underlying mechanism is poorly understood. Here, we describe the specificity of FMDV VP3 interaction with the transmembrane (TM) domain of MAVS as FMDV driven type-I IFN inhibitory mechanism for its effective replication. The TM domain of MAVS governs the mitochondria localization of MAVS, and it is a key factor in type-I IFN signaling transduction via MAVS aggregation. Thereby, the interaction of FMDV VP3 with the TM domain of MAVS leads to the inhibition of MAVS mitochondria localization, self-association, and aggregation, resulting in the suppression of type-I IFN response. Collectively, these results provide a clear understanding of a key molecular mechanism used by the FMDV VP3 for the suppression of IFN responses via targeting MAVS.
Peptide Derivatives of Platelet-Derived Growth Factor Receptor Alpha Inhibit Cell-Associated Spread of Human Cytomegalovirus
Authors: Braun Berenike , Fischer Dina , Laib Sampaio Kerstin , Mezger Maja , Stöhr Dagmar , Stanton Richard James , Sinzger Christian
Published: September 2021

Cell-free human cytomegalovirus (HCMV) can be inhibited by a soluble form of the cellular HCMV-receptor PDGFRα, resembling neutralization by antibodies. The cell-associated growth of recent HCMV isolates, however, is resistant against antibodies. We investigated whether PDGFRα-derivatives can inhibit this transmission mode. A protein containing the extracellular PDGFRα-domain and 40-mer peptides derived therefrom were tested regarding the inhibition of the cell-associated HCMV strain Merlin-pAL1502, hits were validated with recent isolates, and the most effective peptide was modified to increase its potency. The modified peptide was further analyzed regarding its mode of action on the virion level. While full-length PDGFRα failed to inhibit HCMV isolates, three peptides significantly reduced virus growth. A 30-mer version of the lead peptide (GD30) proved even more effective against the cell-free virus, and this effect was HCMV-specific and depended on the viral glycoprotein O. In cell-associated spread, GD30 reduced both the number of transferred particles and their penetration. This effect was reversible after peptide removal, which allowed the synchronized analysis of particle transfer, showing that two virions per hour were transferred to neighboring cells and one virion was sufficient for infection. In conclusion, PDGFRα-derived peptides are novel inhibitors of the cell-associated spread of HCMV and facilitate the investigation of this transmission mode.
Monocytes Exposed to Immune Complexes Reduce pDC Type 1 Interferon Response to Vidutolimod
Authors: Sabree Shakoora A. , Lemke-Miltner Caitlin D. , Blackwell Sue E. , Yin Chaobo , Bossler Aaron , Ebeid Kareem , Salem Aliasger K. , Weiner George J.
Published: September 2021

Vidutolimod, also known as CMP-001, is a virus-like particle composed of the Qβ bacteriophage coat protein encasing a TLR9 agonist. Vidutolimod injected intratumorally is showing promise in early phase clinical trials based on its ability to alter the tumor microenvironment and induce an anti-tumor immune response. We previously demonstrated that the in vivo efficacy of vidutolimod is dependent on the presence of anti-Qβ antibodies that enhance opsonization and uptake of vidutolimod by TLR9-expressing plasmacytoid dendritic cells (pDCs). Here, we evaluated the effect of immune complexes, including anti-Qβ-coated vidutolimod, on induction of Type 1 Interferon production by peripheral blood mononuclear cells in response to vidutolimod and soluble TLR9 agonists. Immune complexes, including but not limited to anti-Qβ-coated vidutolimod, indirectly suppressed TLR9-mediated Type 1 Interferon production by pDCs in a monocyte-dependent manner. These findings indicate that anti-Qβ-coated vidutolimod has effects in addition to those mediated by TLR9 that could have important clinical implications for understanding the mechanism of action of this exciting new approach to in situ immunization and cancer immunotherapy.