bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of Fuzzy AHP and Fuzzy TOPSIS Methods for Wire Electric Discharge Machining of Titanium (Ti6Al4V) Alloy Using RSM
Authors: Fuse Kishan , Dalsaniya Arrown , Modi Dhananj , Vora Jay , Pimenov Danil Yurievich , Giasin Khaled , Prajapati Parth , Chaudhari Rakesh , Wojciechowski Szymon
Published: December 2021

Titanium and its alloys exhibit numerous uses in aerospace, automobile, biomedical and marine industries because of their enhanced mechanical properties. However, the machinability of titanium alloys can be cumbersome due to their lower density, high hardness, low thermal conductivity, and low elastic modulus. The wire electrical discharge machining (WEDM) process is an effective choice for machining titanium and its alloys due to its unique machining characteristics. The present work proposes multi-objective optimization of WEDM on Ti6Al4V alloy using a fuzzy integrated multi-criteria decision-making (MCDM) approach. The use of MCDM has become an active area of research due to its proven ability to solve complex problems. The novelty of the present work is to use integrated fuzzy analytic hierarchy process (AHP) and fuzzy technique for order preference by similarity to ideal situation (TOPSIS) to optimize the WEDM process. The experiments were systematically conducted adapting the face-centered central composite design approach of response surface methodology. Three independent factors—pulse-on time (Ton), pulse-off time (Toff), and current—were chosen, each having three levels to monitor the process response in terms of cutting speed (VC), material removal rate (MRR), and surface roughness (SR). To assess the relevance and significance of the models, an analysis of variance was carried out. The optimal process parameters after integrating fuzzy AHP coupled with fuzzy TOPSIS approach found were Ton = 40 µs, Toff = 15 µs, and current = 2A.
Experimentally Validated Extension of the Operating Range of an Electrically Driven Turbocharger for Fuel Cell Applications
Authors: Schoedel Markus , Menze Marco , Seume Joerg R.
Published: December 2021

From an aerodynamic point of view, the electric turbocharger for the air supply of an automotive fuel cell faces difficult requirements: it must not only control the pressure level of the fuel cell, but it also has to operate with very high efficiency over a wide range. This paper explores features for the compressor and the turbine of an existing electric turbocharger, which are intended to meet the specific requirements of a fuel cell in an experimentally validated numerical study. Adjustable diffuser or nozzle vanes in the compressor and turbine achieve wider operating ranges but compromise efficiency, especially because of the necessary gaps between vanes and end walls. For the turbine, there are additional efficiency losses since the pivoting of the nozzle vanes leads to incidence and thus to flow separation at the leading edge of the nozzle vanes and the rotor blades. An increase in the mass flow and a slight efficiency improvement of the turbine with the low solidity nozzle vanes counteracts these losses. For the compressor, a reduction in the diffuser height and its influence over the operating range and power consumption yields an increase in surge margin as well as in maximum efficiency.
A New Modified Fixed-Point Iteration Process
Authors: Garodia Chanchal , Abdou Afrah A. N. , Uddin Izhar
Published: December 2021

In this paper, we present a new modified iteration process in the setting of uniformly convex Banach space. The newly obtained iteration process can be used to approximate a common fixed point of three nonexpansive mappings. We have obtained strong and weak convergence results for three nonexpansive mappings. Additionally, we have provided an example to support the theoretical proof. In the process, several relevant results are improved and generalized.
ANA: Ant Nesting Algorithm for Optimizing Real-World Problems
Authors: Hama Rashid Deeam Najmadeen , Rashid Tarik A. , Mirjalili Seyedali
Published: December 2021

In this paper, a novel swarm intelligent algorithm is proposed called ant nesting algorithm (ANA). The algorithm is inspired by Leptothorax ants and mimics the behavior of ants searching for positions to deposit grains while building a new nest. Although the algorithm is inspired by the swarming behavior of ants, it does not have any algorithmic similarity with the ant colony optimization (ACO) algorithm. It is worth mentioning that ANA is considered a continuous algorithm that updates the search agent position by adding the rate of change (e.g., step or velocity). ANA computes the rate of change differently as it uses previous, current solutions, fitness values during the optimization process to generate weights by utilizing the Pythagorean theorem. These weights drive the search agents during the exploration and exploitation phases. The ANA algorithm is benchmarked on 26 well-known test functions, and the results are verified by a comparative study with genetic algorithm (GA), particle swarm optimization (PSO), dragonfly algorithm (DA), five modified versions of PSO, whale optimization algorithm (WOA), salp swarm algorithm (SSA), and fitness dependent optimizer (FDO). ANA outperformances these prominent metaheuristic algorithms on several test cases and provides quite competitive results. Finally, the algorithm is employed for optimizing two well-known real-world engineering problems: antenna array design and frequency-modulated synthesis. The results on the engineering case studies demonstrate the proposed algorithm’s capability in optimizing real-world problems.
A First Approach to Closeness Distributions
Authors: Cerquides Jesus
Published: December 2021

Probabilistic graphical models allow us to encode a large probability distribution as a composition of smaller ones. It is oftentimes the case that we are interested in incorporating in the model the idea that some of these smaller distributions are likely to be similar to one another. In this paper we provide an information geometric approach on how to incorporate this information and see that it allows us to reinterpret some already existing models. Our proposal relies on providing a formal definition of what it means to be close. We provide an example on how this definition can be actioned for multinomial distributions. We use the results on multinomial distributions to reinterpret two already existing hierarchical models in terms of closeness distributions.
The Role of New Technological Opportunities and the Need to Evaluate the Activities Performed in the Prevention of Diabetic Foot with Exercise Therapy
Authors: Francia Piergiorgio , De Bellis Alessandra , Iannone Giulia , Sinopoli Rosy , Bocchi Leonardo , Anichini Roberto
Published: December 2021

The diabetic foot (DF) is one of the most feared conditions among chronic complications of diabetes, which affects a growing number of patients. Although exercise therapy (ET) has always been considered a pillar in the treatment of patients at risk of DF it is not usually used. Several causes can contribute to hindering both the organization of ET protocols for Diabetes Units and the participation in ET programs for patients at different levels of risk of foot ulceration. The risk of favoring the occurrence of ulcers and the absence of clear evidence on the role played by ET in the prevention of ulcers could be considered among the most important causes leading to the low application of ET. The increased availability of new technologies and in particular of systems and devices equipped with sensors can enable the remote monitoring and management of physical activity performed by patients. Consequently, they can become an opportunity for introducing the systematic use of ET for the treatment of patients at risk. Considering the complexity of the clinical conditions that patients at risk or with diabetic foot ulcer can show, the evaluation of how patients perform the ET proposed can consequently be very important. All this can contribute to improving the treatment of patients and avoiding possible adverse effects. The aim of this brief review was to describe that the use of new technologies and the assessment of the execution of the ET proposed allows an important step forward in the management of patients at risk.
Untargeted Analysis of Lemna minor Metabolites: Workflow and Prioritization Strategy Comparing Highly Confident Features between Different Mass Spectrometers
Authors: Wahman Rofida , Moser Stefan , Bieber Stefan , Cruzeiro Catarina , Schröder Peter , Gilg August , Lesske Frank , Letzel Thomas
Published: December 2021

Metabolomics approaches provide a vast array of analytical datasets, which require a comprehensive analytical, statistical, and biochemical workflow to reveal changes in metabolic profiles. The biological interpretation of mass spectrometric metabolomics results is still obstructed by the reliable identification of the metabolites as well as annotation and/or classification. In this work, the whole Lemna minor (common duckweed) was extracted using various solvents and analyzed utilizing polarity-extended liquid chromatography (reversed-phase liquid chromatography (RPLC)-hydrophilic interaction liquid chromatography (HILIC)) connected to two time-of-flight (TOF) mass spectrometer types, individually. This study (introduces and) discusses three relevant topics for the untargeted workflow: (1) A comparison study of metabolome samples was performed with an untargeted data handling workflow in two different labs with two different mass spectrometers using the same plant material type. (2) A statistical procedure was observed prioritizing significant detected features (dependent and independent of the mass spectrometer using the predictive methodology Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA). (3) Relevant features were transferred to a prioritization tool (the FOR-IDENT platform (FI)) and were compared with the implemented compound database PLANT-IDENT (PI). This compound database is filled with relevant compounds of the Lemnaceae, Poaceae, Brassicaceae, and Nymphaceae families according to analytical criteria such as retention time (polarity and LogD (pH 7)) and accurate mass (empirical formula). Thus, an untargeted analysis was performed using the new tool as a prioritization and identification source for a hidden-target screening strategy. Consequently, forty-two compounds (amino acids, vitamins, flavonoids) could be recognized and subsequently validated in Lemna metabolic profile using reference standards. The class of flavonoids includes free aglycons and their glycosides. Further, according to our knowledge, the validated flavonoids robinetin and norwogonin were for the first time identified in the Lemna minor extracts.
Discovering the Next-Generation Plant Protection Products: A Proof-of-Concept via the Isolation and Bioactivity Assessment of the Olive Tree Endophyte Bacillus sp. PTA13 Lipopeptides
Authors: Papadopoulou Evgenia-Anna , Angelis Apostolis , Antoniadi Lemonia , Aliferis Konstantinos A. , Skaltsounis Alexios-Leandros
Published: December 2021

Endophytic microorganisms (EMs) have recently attracted interest for applications in plant protection, mainly due to their bioactive compound-producing capacity. Therefore, we underwent the task of isolating olive tree EMs and investigating their bioactivity against the devastating pathogen Colletotrichum acutatum. Several EMs were isolated; however, the Bacillus sp. PTA13 isolate exhibited the highest toxicity to the phytopathogen. Bacteria of the genus Bacillus exhibit superior bioactive metabolite-producing capacity, with the lipopeptides (LPs) of surfactin, iturin, and fengycin groups being the most studied. A total LP extract and several fractions were obtained, and their bioactivity was assessed against C. acutatum strains. LPs of the major surfactin, iturin, and fengycin groups and the minor gageotetrin and bacilotetrin groups were annotated. The results confirmed the bioactivity of the major LPs, with fengycins being the most fungitoxic. Interestingly, the minor LP fraction exhibited selective toxicity to the fungicide-resistant C. acutatum isolate, an observation that highlights the significance of our approach to comprehensively mine the total LP extract. This work represents a proof of concept of the exploitation of EMs in customized olive tree plant protection and aligns well with strategies that focus on the sustainability and safety of food production via the development of next-generation plant protection products.
Factors Influencing the Fungal Diversity on Audio–Visual Materials
Authors: Branysova Tereza , Kracmarova Martina , Durovic Michal , Demnerova Katerina , Stiborova Hana
Published: December 2021

The biodeterioration of audio–visual materials is a huge problem, as it can cause incalculable losses. To preserve these cultural heritage objects for future generations, it is necessary to determine the main agents of biodeterioration. This study focuses on identifying fungi, both from the air and smears from photographs and cinematographic films that differ in the type of carrier and binder, using high-throughput sequencing approaches. The alpha diversity measures of communities present on all types of carriers were compared, and a significant difference between cellulose acetate and baryta paper was observed. Next, the locality, type of carrier, and audio–visual material seem to affect the structure of fungal communities. Additionally, a link between the occurrence of the most abundant classes and species on audio–visual materials and air contamination in the archives was proven. In both cases, the most abundant classes were Agariomycetes, Dothideomycetes, and Eurotiomycetes, and approximately half of the 50 most abundant species detected on the audio–visual materials and in the air were identical.
Antileishmanial Drug Discovery and Development: Time to Reset the Model?
Authors: Olías-Molero Ana Isabel , de la Fuente Concepción , Cuquerella Montserrat , Torrado Juan J. , Alunda José M.
Published: December 2021

Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The disease affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the Leishmania sp. and the host immune response. No vaccine for humans is available, and the control relies mainly on chemotherapy. However, currently used drugs are old, some are toxic, and the safer presentations are largely unaffordable by the most severely affected human populations. Moreover, its efficacy has shortcomings, and it has been challenged by the growing reports of resistance and therapeutic failure. This manuscript presents an overview of the currently used drugs, the prevailing model to develop new antileishmanial drugs and its low efficiency, and the impact of deconstruction of the drug pipeline on the high failure rate of potential drugs. To improve the predictive value of preclinical research in the chemotherapy of leishmaniasis, several proposals are presented to circumvent critical hurdles—namely, lack of common goals of collaborative research, particularly in public–private partnership; fragmented efforts; use of inadequate surrogate models, especially for in vivo trials; shortcomings of target product profile (TPP) guides.
Investigation of Transovarial Transmission of Bartonella henselae in Rhipicephalus sanguineus sensu lato Ticks Using Artificial Feeding
Authors: Wechtaisong Wittawat , Bonnet Sarah I. , Chomel Bruno B. , Lien Yi-Yang , Chuang Shih-Te , Tsai Yi-Lun
Published: December 2021

Bartonella henselae is a slow-growing, Gram-negative bacterium that causes cat scratch disease in humans. A transstadial transmission of the bacteria from larvae to nymphs of Rhipicephalus sanguineus sensu lato (s.l.) ticks, suspected to be a potential vector of the bacteria, has been previously demonstrated. The present study aims to investigate transovarial transmission of B. henselae from R. sanguineus s.l. adults to their instars. Adult ticks (25 males and 25 females) were fed through an artificial feeding system on B. henselae-infected goat blood for 14 days, and 300 larvae derived from the experimentally B. henselae-infected females were fed on noninfected goat blood for 7 days. Nested PCR and culture were used to detect and isolate B. henselae in ticks and blood samples. Bartonella henselae DNA was detected in midguts, salivary glands, and carcasses of the semi-engorged adults and pooled tick feces (during feeding and post-feeding periods). After the oviposition period, B. henselae DNA was detected in salivary glands of females (33.3%), but not in pooled eggs or larvae derived from the infected females. However, B. henselae DNA was detected by nested PCR from the blood sample during larval feeding, while no viable B. henselae was isolated by culture. According to our findings, following infected blood meal, B. henselae could remain in the tick midguts, move to other tissues including salivary glands, and then be shed through tick feces with limited persistency. The presence of bacterial DNA in the blood during larval feeding shows the possibility of transovarial transmission of B. henselae in R. sanguineus s.l. ticks.
Priming of Resistance-Related Phenolics: A Study of Plant-Associated Bacteria and Hymenoscyphus fraxineus
Authors: Striganavičiūtė Greta , Žiauka Jonas , Sirgedaitė-Šėžienė Vaida , Vaitiekūnaitė Dorotėja
Published: December 2021

European ash (Fraxinus excelsior) is highly affected by the pathogenic fungus Hymenoscyphus fraxineus in all of Europe. Increases in plant’s secondary metabolite (SM) production is often linked tol enhanced resistance to stress, both biotic and abiotic. Moreover, plant-associated bacteria have been shown to enhance SM production in inoculated plants. Thus, our hypothesis is that bacteria may boost ash SM production, hence priming the tree’s metabolism and facilitating higher levels of resilience to H. fraxineus. We tested three different ash genotypes and used Paenibacillus sp. and Pseudomonas sp. for inoculation in vitro. Total phenol (TPC), total flavonoid (TFC) and carotenoid contents were measured, as well as the chlorophyll a/b ratio and morphometric growth parameters, in a two-stage trial, whereby seedlings were inoculated with the bacteria during the first stage and with H. fraxineus during the second stage. While the tested bacteria did not positively affect the morphometric growth parameters of ash seedlings, they had a statistically significant effect on TPC, TFC, the chlorophyll a/b ratio and carotenoid content in both stages, thus confirming our hypothesis. Specifically, in ash genotype 64, both bacteria elicited an increase in carotenoid content, TPC and TFC during both stages. Additionally, Pseudomonas sp. inoculated seedlings demonstrated an increase in phenolics after infection with the fungus in both genotypes 64 and 87. Our results indicate that next to genetic selection of the most resilient planting material for ash reforestation, plant-associated bacteria could also be used to boost ash SM production.
Coal Moisture Variations in Response to Rainfall Event in Mines and Coal-Fired Power Plant Stockpiles—Part 1: Runoff, Infiltration, and Drainage
Authors: Campbell Quentin Peter , le Roux Marco , Nakhaei Fardis
Published: December 2021

Excessive coal moisture leads to a lower heating value and power plant efficiency, and increased transportation costs. Therefore, coal stockpile management and moisture control are particularly important in regions with heavy precipitation. This paper and Part 2 address factors influencing moisture retention and migration in coal stockpiles. Part 1 of this paper series simulates phenomena of runoff, infiltration, and drainage in a stockpile after a rainfall event. Part 2 reports the effect of coal particle size and climate conditions on the rate and depth of moisture evaporation process within a coal stockpile. To perform this study, two coal samples were collected from the Witbank mine in South Africa. The results of the present study showed that smaller interparticulate void spaces because of the compaction or fines particles (−0.5 mm fraction) inhibited infiltration, leading to increased runoff volume. An increase stockpile slope increased the amount of runoff due to coal–water contact time reduction. The ability of heavy rainfall to destroy near-surface structures (erosion) happened more readily at stockpiles with high slopes and high fine content. The fine content significantly influenced the dewatering efficiency of drainage. Coals with higher ash contents had stronger moisture retention ability than that of other coals even though coals with low ash contents had a high fine content. This was ascribed to the contribution of the clay minerals, such as kaolinite, in the high ash coal. The results of this paper can be used for the effective management of coal stockpiles to prevent excessive moisture in stockpiles for the best possible utilisation of coal in power plants.
Influence of Liquid Crystallinity and Mechanical Deformation on the Molecular Relaxations of an Auxetic Liquid Crystal Elastomer
Authors: Raistrick Thomas , Reynolds Matthew , Gleeson Helen F. , Mattsson Johan
Published: December 2021

Liquid Crystal Elastomers (LCEs) combine the anisotropic ordering of liquid crystals with the elastic properties of elastomers, providing unique physical properties, such as stimuli responsiveness and a recently discovered molecular auxetic response. Here, we determine how the molecular relaxation dynamics in an acrylate LCE are affected by its phase using broadband dielectric relaxation spectroscopy, calorimetry and rheology. Our LCE is an excellent model system since it exhibits a molecular auxetic response in its nematic state, and chemically identical nematic or isotropic samples can be prepared by cross-linking. We find that the glass transition temperatures (Tg) and dynamic fragilities are similar in both phases, and the T-dependence of the α relaxation shows a crossover at the same T* for both phases. However, for T>T*, the behavior becomes Arrhenius for the nematic LCE, but only more Arrhenius-like for the isotropic sample. We provide evidence that the latter behavior is related to the existence of pre-transitional nematic fluctuations in the isotropic LCE, which are locked in by polymerization. The role of applied strain on the relaxation dynamics and mechanical response of the LCE is investigated; this is particularly important since the molecular auxetic response is linked to a mechanical Fréedericksz transition that is not fully understood. We demonstrate that the complex Young’s modulus and the α relaxation time remain relatively unchanged for small deformations, whereas for strains for which the auxetic response is achieved, significant increases are observed. We suggest that the observed molecular auxetic response is coupled to the strain-induced out-of-plane rotation of the mesogen units, in turn driven by the increasing constraints on polymer configurations, as reflected in increasing elastic moduli and α relaxation times; this is consistent with our recent results showing that the auxetic response coincides with the emergence of biaxial order.
DeepNGlyPred: A Deep Neural Network-Based Approach for Human N-Linked Glycosylation Site Prediction
Authors: Pakhrin Subash C. , Aoki-Kinoshita Kiyoko F. , Caragea Doina , KC Dukka B.
Published: December 2021

Protein N-linked glycosylation is a post-translational modification that plays an important role in a myriad of biological processes. Computational prediction approaches serve as complementary methods for the characterization of glycosylation sites. Most of the existing predictors for N-linked glycosylation utilize the information that the glycosylation site occurs at the N-X-[S/T] sequon, where X is any amino acid except proline. Not all N-X-[S/T] sequons are glycosylated, thus the N-X-[S/T] sequon is a necessary but not sufficient determinant for protein glycosylation. In that regard, computational prediction of N-linked glycosylation sites confined to N-X-[S/T] sequons is an important problem. Here, we report DeepNGlyPred a deep learning-based approach that encodes the positive and negative sequences in the human proteome dataset (extracted from N-GlycositeAtlas) using sequence-based features (gapped-dipeptide), predicted structural features, and evolutionary information. DeepNGlyPred produces SN, SP, MCC, and ACC of 88.62%, 73.92%, 0.60, and 79.41%, respectively on N-GlyDE independent test set, which is better than the compared approaches. These results demonstrate that DeepNGlyPred is a robust computational technique to predict N-Linked glycosylation sites confined to N-X-[S/T] sequon. DeepNGlyPred will be a useful resource for the glycobiology community.
OSMAC Strategy Integrated with Molecular Networking for Accessing Griseofulvin Derivatives from Endophytic Fungi of Moquiniastrum polymorphum (Asteraceae)
Authors: Farinella Victor F. , Kawafune Eunizinis S. , Tangerina Marcelo M. P. , Domingos Helori V. , Costa-Lotufo Leticia V. , Ferreira Marcelo J. P.
Published: December 2021

Three endophytic fungi isolated from Moquiniastrum polymorphum (Less.) G. Sancho (Asteraceae) were cultivated using the one strain many compounds (OSMAC) strategy to evaluate the production of griseofulvin derivatives. Extracts obtained were analyzed by HPLC–MS/MS and the chromatographic and spectrometric data used to elaborate a feature-based molecular network (FBMN) through the GNPS platform. This approach allowed the observation of differences such as medium-specific and strain-specific production of griseofulvin derivatives and variations of cytotoxic activity in most extracts. To evaluate the efficiency of the OSMAC approach allied with FBMN analysis in the prospection of compounds of biotechnological interest, griseofulvin and 7-dechlorogriseofulvin were isolated, and the relative concentrations were estimated in all culture media using HPLC–UV, allowing for the inference of the best strain–medium combinations to maximize its production. Malt extract-peptone broth and Wickerham broth media produced the highest concentrations of both secondary metabolites.
Reductive Hydroformylation of Isosorbide Diallyl Ether
Authors: Ternel Jérémy , Lopes Adrien , Sauthier Mathieu , Buffe Clothilde , Wiatz Vincent , Bricout Hervé , Tilloy Sébastien , Monflier Eric
Published: December 2021

Isosorbide and its functionalized derivatives have numerous applications as bio-sourced building blocks. In this context, the synthesis of diols from isosorbide diallyl ether by hydrohydroxymethylation reaction is of extreme interest. This hydrohydroxymethylation, which consists of carbon-carbon double bonds converting into primary alcohol functions, can be obtained by a hydroformylation reaction followed by a hydrogenation reaction. In this study, reductive hydroformylation was achieved using isosorbide diallyl ether as a substrate in a rhodium/amine catalytic system. The highest yield in bis-primary alcohols obtained was equal to 79%.
Drug Repurposing for Influenza Virus Polymerase Acidic (PA) Endonuclease Inhibitor
Authors: Meng Xin , Wang Ye
Published: December 2021

Drug repurposing can quickly and effectively identify novel drug repurposing opportunities. The PA endonuclease catalytic site has recently become regarded as an attractive target for the screening of anti-influenza drugs. PA N-terminal (PAN) inhibitor can inhibit the entire PA endonuclease activity. In this study, we screened the effectivity of PAN inhibitors from the FDA database through in silico methods and in vitro experiments. PAN and mutant PAN-I38T were chosen as virtual screening targets for overcoming drug resistance. Gel-based PA endonuclease analysis determined that the drug lifitegrast can effectively inhibit PAN and PAN-I38T, when the IC50 is 32.82 ± 1.34 μM and 26.81 ± 1.2 μM, respectively. Molecular docking calculation showed that lifitegrast interacted with the residues around PA or PA-I38 T’s active site, occupying the catalytic site pocket. Both PAN/PAN-I38T and lifitegrast can acquire good equilibrium in 100 ns molecular dynamic simulation. Because of these properties, lifitegrast, which can effectively inhibit PA endonuclease activity, was screened through in silico and in vitro research. This new research will be of significance in developing more effective and selective drugs for anti-influenza therapy.
Molecular Mechanisms of Anticancer Activity of N-Glycosides of Indolocarbazoles LCS-1208 and LCS-1269
Authors: Zenkov Roman G. , Vlasova Olga A. , Maksimova Varvara P. , Fetisov Timur I. , Karpechenko Natalia Y. , Ektova Lidiya V. , Eremina Vera A. , Popova Valeriia G. , Usalka Olga G. , Lesovaya Ekaterina A. , Belitsky Gennady A. , Yakubovskaya Marianna G. , Kirsanov Kirill I.
Published: December 2021

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed–the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated—LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.
Impact of Pre-Patterned Structures on Features of Laser-Induced Periodic Surface Structures
Authors: Maragkaki Stella , Lingos Panagiotis C. , Tsibidis George D. , Deligeorgis George , Stratakis Emmanuel
Published: December 2021

The efficiency of light coupling to surface plasmon polariton (SPP) represents a very important issue in plasmonics and laser fabrication of topographies in various solids. To illustrate the role of pre-patterned surfaces and impact of laser polarisation in the excitation of electromagnetic modes and periodic pattern formation, Nickel surfaces are irradiated with femtosecond laser pulses of polarisation perpendicular or parallel to the orientation of the pre-pattern ridges. Experimental results indicate that for polarisation parallel to the ridges, laser induced periodic surface structures (LIPSS) are formed perpendicularly to the pre-pattern with a frequency that is independent of the distance between the ridges and periodicities close to the wavelength of the excited SPP. By contrast, for polarisation perpendicular to the pre-pattern, the periodicities of the LIPSS are closely correlated to the distance between the ridges for pre-pattern distance larger than the laser wavelength. The experimental observations are interpreted through a multi-scale physical model in which the impact of the interference of the electromagnetic modes is revealed.
Heat and Mass Transfer in an Adsorbed Natural Gas Storage System Filled with Monolithic Carbon Adsorbent during Circulating Gas Charging
Authors: Strizhenov Evgeny M. , Chugaev Sergey S. , Men’shchikov Ilya E. , Shkolin Andrey V. , Zherdev Anatoly A.
Published: December 2021

Adsorbed natural gas (ANG) technology is a promising alternative to traditional compressed (CNG) and liquefied (LNG) natural gas systems. Nevertheless, the energy efficiency and storage capacity of an ANG system strongly depends on the thermal management of its inner volume because of significant heat effects occurring during adsorption/desorption processes. In the present work, a prototype of a circulating charging system for an ANG storage tank filled with a monolithic nanoporous carbon adsorbent was studied experimentally under isobaric conditions (0.5–3.5 MPa) at a constant volumetric flow rate (8–18 m3/h) or flow mode (Reynolds number at the adsorber inlet from 100,000 to 220,000). The study of the thermal state of the monolithic adsorbent layer and internal heat exchange processes during the circulating charging of an adsorbed natural gas storage system was carried out. The correlation between the gas flow mode, the dynamic gas flow temperature, and the heat transfer coefficient between the gas and adsorbent was determined. A one-dimensional mathematical model of the circulating low-temperature charging process was developed, the results of which correspond to the experimental measurements.
Fruit and Vegetable Supplemented Diet Modulates the Pig Transcriptome and Microbiome after a Two-Week Feeding Intervention
Authors: Solano-Aguilar Gloria , Lakshman Sukla , Shao Jonathan , Chen Celine , Beshah Ethiopia , Dawson Harry , Vinyard Bryan , Schroeder Steven , Jang Saebyeol , Molokin Aleksey , Urban Joseph
Published: December 2021

A study was conducted to determine the effects of a diet supplemented with fruits and vegetables (FV) on the host whole blood cell (WBC) transcriptome and the composition and function of the intestinal microbiome. Nine six-week-old pigs were fed a pig grower diet alone or supplemented with lyophilized FV equivalent to half the daily recommended amount prescribed for humans by the Dietary Guideline for Americans (DGA) for two weeks. Host transcriptome changes in the WBC were evaluated by RNA sequencing. Isolated DNA from the fecal microbiome was used for 16S rDNA taxonomic analysis and prediction of metabolomic function. Feeding an FV-supplemented diet to pigs induced differential expression of several genes associated with an increase in B-cell development and differentiation and the regulation of cellular movement, inflammatory response, and cell-to-cell signaling. Linear discriminant analysis effect size (LEfSe) in fecal microbiome samples showed differential increases in genera from Lachnospiraceae and Ruminococcaceae families within the order Clostridiales and Erysipelotrichaceae family with a predicted reduction in rgpE-glucosyltransferase protein associated with lipopolysaccharide biosynthesis in pigs fed the FV-supplemented diet. These results suggest that feeding an FV-supplemented diet for two weeks modulated markers of cellular inflammatory and immune function in the WBC transcriptome and the composition of the intestinal microbiome by increasing the abundance of bacterial taxa that have been associated with improved intestinal health.
From Screening to Therapy: Anti-HCV Screening and Linkage to Care in a Network of General Practitioners and a Private Gastroenterology Practice
Authors: Petroff David , Bätz Olaf , Jedrysiak Katrin , Lüllau Anja , Kramer Jan , Möller Hjördis , Heyne Renate , Jäger Burkhard , Berg Thomas , Wiegand Johannes
Published: December 2021

(1) Background: Low rates of hepatitis C virus (HCV) diagnosis and sub-optimal linkage to care constitute barriers toward eliminating the infection. In 2012/2013, we showed that HCV screening in primary care detects unknown cases. However, hepatitis C patients may not receive further diagnostics and therapy because they drop out during the referral pathway to secondary care. Thus, we used an existing network of primary care physicians and a practice of gastroenterology to investigate the pathway from screening to therapy. (2) Methods: HCV screening was prospectively included in a routine check-up of primary care physicians who cooperated regularly with a private gastroenterology practice. Anti-HCV-positive patients were referred for further specialized diagnostics and treatment if indicated. (3) Results: Seventeen primary care practices screened 1875 patients. Twelve individuals were anti-HCV-positive (0.6%), six of them reported previous antiviral HCV therapy, and one untreated patient was HCV-RNA-positive (0.05% of the population). None of the 12 anti-HCV-positive cases showed up at the private gastroenterology practice. Further clinical details of the pathway from screening to therapy could not be analyzed. (4) Conclusions: The linkage between primary and secondary care appears to be problematic in the HCV setting even among cooperating partners, but robust conclusions require larger datasets.
Antirheumatic Drugs against COVID-19 from the Perspective of Rheumatologists
Authors: Kawazoe Mai , Kihara Mari , Nanki Toshihiro
Published: December 2021

Coronavirus disease 2019 (COVID-19) remains a global threat to humanity. Its pathogenesis and different phases of disease progression are being elucidated under the pandemic. Active viral replication activates various immune cells and produces large amounts of inflammatory cytokines, which leads to the cytokine storm, a major cause of patient death. Therefore, viral inhibition is expected to be the most effective early in the course of the disease, while immunosuppressive treatment may be useful in the later stages to prevent disease progression. Based on the pathophysiology of rheumatic diseases, various immunomodulatory and immunosuppressive drugs are used for the diseases. Due to their mechanism of action, the antirheumatic drugs, including hydroxychloroquine, chloroquine, colchicine, calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), glucocorticoids, cytokines inhibitors, such as anti-tumor necrosis factor-α (e.g., infliximab), anti-interleukin (IL)-6 (e.g., tocilizumab, sarilumab, and siltuximab), anti-IL-1 (e.g., anakinra and canakinumab) and Janus kinase inhibitors (e.g., baricitinib and tofacitinib), cytotoxic T lymphocyte-associated antigen 4 blockade agents (e.g., abatacept), and phosphodiesterase 4 inhibitors (e.g., apremilast), have been tried as a treatment for COVID-19. In this review, we discuss the mechanisms of action and clinical impact of these agents in the management of COVID-19.
Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity
Authors: Singh Kuljeet , Tarapcsák Szabolcs , Gyöngy Zsuzsanna , Ritter Zsuzsanna , Batta Gyula , Bosire Rosevalentine , Remenyik Judit , Goda Katalin
Published: December 2021

P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.
Numerical Analysis of Optical Trapping Force Affected by Lens Misalignments
Authors: Zhang Hanlin , Li Wenqiang , Li Nan , Hu Huizhu
Published: December 2021

Geometrical optics approximation is a classic method for calculating the optical trapping force on particles whose sizes are larger than the wavelength of the trapping light. In this study, the effect of the lens misalignment on optical force was analyzed in the geometrical optics regime. We used geometrical optics to analyze the influence of off-axis placement and the tilt of the lens on the trapping position and stiffness in an optical trap. Numerical calculation results showed that lens tilting has a greater impact on the optical trap force than the off-axis misalignments, and both misalignments will couple with each other and cause a shift of the equilibrium point and the asymmetry of the optical trap stiffness in different ways. Our research revealed the asymmetry in optical traps caused by lens misalignment and can provide guidance for optimize lens placement in future experiments.
Talking about premature ejaculation in primary care: the GET UP cluster randomised controlled trial
Authors: Barais Marie , Costa Marine , Montalvo Camille , Rannou Vincent , Vaillant-Roussel Hélène , Costa David , Cadier Sébastien , Pereira Bruno
Published: December 2021

Background

Premature ejaculation (PE) is the most common sexual dysfunction in males. A previous qualitative study identified six communication strategies described by GPs to tackle this topic during consultations.

Aim

To determine whether these six strategies are more effective than usual care for promoting discussion about PE between patients and their GPs.

Design and setting

Cluster randomised controlled trial, stratified in four French regions, with an intervention group (GPs who received a training session on the six communication strategies) and a control group (routine medical care). Participants were males aged 18–80 years consulting for a sexual, urogenital, or psychological reason.

Method

The efficacy of the training session in communication skills, compared with usual care, was evaluated by determining the percentage of patients who discussed PE with their GP (primary outcome). The percentage of enrolled patients with PE was calculated using a cut-off score >9 of the premature ejaculation diagnostic tool (PEDT) completed by the enrolled patients at Week 4 after the consultation. The quality-of-life changes were evaluated as the SF-12 scale score difference between baseline and Week 4 post-consultation.

Results

In total, 130 patients were included by 32 GPs (n= 16 in the intervention andn= 16 in the control group). The percentage of patients who discussed PE was higher in the intervention group than in the control group (42.0% versus 4.9%, absolute difference = 37.1%; 95% confidence intervals [CI] = 24% to 50%,P<0.001).

Conclusion

Training GPs in communication strategies about PE improves its detection.
Implementation of remote asthma consulting in general practice in response to the COVID-19 pandemic: an evaluation using extended Normalisation Process Theory
Authors: Stewart Jonathan , McCorry Noleen , Reid Helen , Hart Nigel , Kee Frank
Published: December 2021

Background

The COVID-19 pandemic has led to the rapid and reactive deployment of remote consulting in UK general practice. The delivery of acute and chronic asthma care has been affected. Extended Normalisation Process Theory (eNPT) provides a framework for evaluating the implementation of new complex interventions in routine practice, including examination of how context–intervention interactions affect implementation.

Aim

To explore the implementation of remote asthma consulting in UK general practice in response to the COVID-19 pandemic.

Design & setting

Mixed-methods evaluation, which was informed by eNPT, in general practice in Northern Ireland.

Method

Data were collected from a range of healthcare professionals who provide asthma care using online questionnaires, interviews, and multidisciplinary focus groups. Analysis was informed by eNPT.

Results

Ten themes were identified to describe and explain the contribution of general practice staff to implementation of remote asthma consulting. Staff identified novel alternatives to in-person review. Having a practice champion to drive implementation forward, and engage other practice staff, was important. Patient, staff, and healthcare system-contextual factors influencing implementation were identified including access to, understanding of, and willingness to use the technology required for remote consulting.

Conclusion

The experiences of frontline healthcare professionals in this study indicate that remote asthma consulting has potential benefits in terms of access and effectiveness when implementation integrates seamlessly with face-to-face care for those who want or need it. Work is required at practice and healthcare system levels to realise this potential, and ensure implementation does not exacerbate existing healthcare inequalities.
Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model
Authors: Kaseda Shota , Sannomiya Yuya , Horizono Jun , Kuwazuru Jun , Suico Mary Ann , Ogi Sayaka , Sasaki Ryoko , Sunamoto Hidetoshi , Fukiya Hirohiko , Nishiyama Hayato , Kamura Misato , Niinou Saki , Koyama Yuimi , Nara Futoshi , Shuto Tsuyoshi , Onuma Kazuhiro , Kai Hirofumi
Published: December 2021

Background

Bardoxolone methyl activates nuclear factor erythroid 2–related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored.

Methods

We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model (Col4a5-G5X).

Results

Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change.

Conclusions

UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD.