bluuebunny/crossref_metadata_2025 huggingface dataset:
First-Order Approximate Mei Symmetries and Invariants of the Lagrangian
Authors: Kausar Umara , Feroze Tooba
Published: February 2022

In this article, the formulation of first-order approximate Mei symmetries and Mei invariants of the corresponding Lagrangian is presented. Theorems and determining equations are given to evaluate approximate Mei symmetries, as well as approximate first integrals corresponding to each symmetry of the associated Lagrangian. The formulated procedure is explained with the help of the linear equation of motion of a damped harmonic oscillator (DHO). The Mei symmetries corresponding to the Lagrangian and Hamiltonian of DHO are compared.
Hybrid Finite Element Method to Thermo-Elastic Interactions in a Piezo-Thermo-Elastic Medium under a Fractional Time Derivative Model
Authors: Saeed Tareq
Published: February 2022

In this work, the effect of the fractional time derivative on the piezo-thermo-elastic medium is studied, using the hybrid Laplace transform and finite element methods (LFEM). The generalized fractional piezoelectric–thermoelastic basic equations for piezo-thermo-elastic medium are formulated. The Laplace transforms are used for the time derivatives, and the finite element method is used to discretize for the space derivatives. The inversions process is performed using the Stehfest numerical technique. The finite element approach is used to obtain the solutions of complex coupled formulations of this problem. The effects of fractional time derivative and thermal relaxation time on piezoelectric–thermoelastic mediums are studied. It can be seen from the distribution that the thermal-induced displacement, the temperature and the stress of the medium increase at a high fractional parameter.
On the Use of Quadrilateral Meshes for Enhanced Analysis of Waveguide Devices with Manhattan-Type Geometry Cross-Sections
Authors: Rasekhmanesh Mohamad Hosein , Garcia-Contreras Gines , Córcoles Juan , Ruiz-Cruz Jorge A.
Published: February 2022

This work addresses the suitability of using structured meshes composed of quadrilateral finite elements, instead of the classical unstructured meshes made of triangular elements. These meshes are used in the modal analysis of waveguides with Manhattan-like cross-sections. For this problem, solved with the two-dimensional Finite Element Method, there are two main quality metrics: eigenvalue and eigenvector accuracy. The eigenvalue accuracy is first considered, showing how the proposed structured meshes are, given comparable densities, better, especially when dealing with waveguides presenting pairs of modes with the same cutoff frequency. The second metric is measured through a practical problem, which commonly appears in microwave engineering: discontinuity analysis. In this problem, for which the Mode-Matching technique is used, eigenvectors are needed to compute the coupling between the modes in the discontinuities, directly influencing the quality of the transmission and reflection parameters. In this case, it is found that the proposed analysis performs better given low-density meshes and mode counts, thus proving that quadrilateral-element structured meshes are more resilient than their triangular counterparts to higher-order eigenvectors.
A Three-Stage ACO-Based Algorithm for Parallel Batch Loading and Scheduling Problem with Batch Deterioration and Rate-Modifying Activities
Authors: Jang Jae Won , Kim Yong Jae , Kim Byung Soo
Published: February 2022

This paper addresses a batch loading and scheduling problem of minimizing the makespan on parallel batch processing machines. For batch loading, jobs with compatible families can be assigned to the same batch process even if they differ in size; however, batches can only be formed from jobs within the same family, and the batch production time is determined by the family. During the batch scheduling, the deterioration effects are continuously added to batches processed in each parallel machine so that the batch production times become deteriorated. The deteriorated processing time of batches can be recovered to the original processing times of batches by a maintenance or cleaning process of machines. In this problem, we sequentially determine the batching of jobs and the scheduling of batches. Due to the complexity of the problem, we proposed a three-stage ant colony optimization algorithm. The proposed algorithm found an optimal solution for small-sized problems and achieved near-optimal solutions and better performance than a genetic algorithm or a particle swarm optimization for large-sized problems.
A Time-Delayed Deterministic Model for the Spread of COVID-19 with Calibration on a Real Dataset
Authors: Nastasi Giovanni , Perrone Carla , Taffara Salvatore , Vitanza Giorgia
Published: February 2022

During the evolution of the COVID-19 pandemic, each country has adopted different control measures to contrast the epidemic’s diffusion. Restrictions to mobility, public transport, and social life in general have been actuated to contain the spread of the pandemic. In this paper, we consider the deterministic SIRD model with delays proposed by Calleri et al., which is improved by adding the vaccinated compartment V (SIRDV model) and considering a time-dependent contact frequency. The three delays take into account the incubation time of the disease, the healing time, and the death time. The aim of this work is to study the effect of the vaccination campaigns in Great Britain (GBR) and Israel (ISR) during the pandemic period. The different restriction periods are included by fitting the contact frequency on real datasets as a piecewise constant function. As expected, the vaccination campaign reduces the amount of deaths and infected people. Furthermore, for the different levels of restriction policy, we find specific values of the contact frequency that can be used to predict the trend of the pandemic.
Distributed Fusion Estimation in Network Systems Subject to Random Delays and Deception Attacks
Authors: García-Ligero María Jesús , Hermoso-Carazo Aurora , Linares-Pérez Josefa
Published: February 2022

This paper focuses on the distributed fusion estimation problem in which a signal transmitted over wireless sensor networks is subject to deception attacks and random delays. We assume that each sensor can suffer attacks that may corrupt and/or modify the output measurements. In addition, communication failures between sensors and their local processors can delay the receipt of processed measurements. The randomness of attacks and transmission delays is modelled by different Bernoulli random variables with known probabilities of success. According to these characteristics of the sensor networks and assuming that the measurement noises are cross-correlated at the same time step between sensors and are also correlated with the signal at the same and subsequent time steps, we derive a fusion estimation algorithm, including prediction and filtering, using the distributed fusion method. First, for each sensor, the local least-squares linear prediction and filtering algorithm are derived, using a covariance-based approach. Then, the distributed fusion predictor and the corresponding filter are obtained as the matrix-weighted linear combination of corresponding local estimators, checking that the mean squared error is minimised. A simulation example is then given to illustrate the effectiveness of the proposed algorithms.
Diverse Secondary Metabolites from the Coral-Derived Fungus Aspergillus hiratsukae SCSIO 5Bn1003
Authors: Zeng Qi , Chen Yuchan , Wang Junfeng , Shi Xuefeng , Che Yihao , Chen Xiayu , Zhong Weimao , Zhang Weimin , Wei Xiaoyi , Wang Fazuo , Zhang Si
Published: February 2022

Three new metabolites, including a cyclic tetrapeptide asperhiratide (1), an ecdysteroid derivative asperhiratine (2), and a sesquiterpene lactone asperhiratone (3), were isolated and identified from the soft coral-derived fungus Aspergillus hiratsukae SCSIO 5Bn1003, together with 10 known compounds. Their structures were elucidated via spectroscopic analysis, X-ray diffraction analysis, and electronic circular dichroism calculations. In addition, the absolute configuration of 1 was determined by Marfey’s technique and an analysis of the acid hydrolysates using a chiral phase HPLC column. Among all the compounds, 6 and 8 showed medium cytotoxic activities against four tumor cell lines (SF-268, HepG-2, MCF-7, and A549), with IC50 values ranging from 31.03 ± 3.04 to 50.25 ± 0.54 µM. Meanwhile, they strongly inhibited α-glucosidase activities, with IC50 values of 35.73 ± 3.94 and 22.00 ± 2.45 µM, which were close to and even stronger than the positive control acarbose (IC50 = 32.92 ± 1.03 µM). Compounds 6–8 showed significant antibacterial activities against Bacillus subtilis, with MIC values of 10.26 ± 0.76 µM, 17.00 ± 1.25 µM, and 5.30 ± 0.29 µM, respectively. Compounds 9 and 12 exhibited potent radical scavenging activities against DPPH, with IC50 values of 12.23 ± 0.78 µM and 7.38 ± 1.16 µM. In addition, asperhiratide (1) was evaluated for anti-angiogenic activities in the in vivo zebrafish model, which showed a weak inhibitory effect on intersegmental vessel (ISV) formation.
Chitosan and Hyaluronic Acid Nanoparticles as Vehicles of Epoetin Beta for Subconjunctival Ocular Delivery
Authors: Silva Beatriz , Gonçalves Lídia M. , Braz Berta São , Delgado Esmeralda
Published: February 2022

Neuroprotection in glaucoma using epoetin beta (EPOβ) has yielded promising results. Our team has developed chitosan-hyaluronic acid nanoparticles (CS/HA) designed to carry EPOβ into the ocular globe, improving the drug’s mucoadhesion and retention time on the ocular surface to increase its bioavailability. In the present in vivo study, we explored the possibility of delivering EPOβ to the eye through subconjunctival administration of chitosan-hyaluronic acid-EPOβ (CS/HA-EPOβ) nanoparticles. Healthy Wistar Hannover rats (n = 21) were split into 7 groups and underwent complete ophthalmological examinations, including electroretinography and microhematocrit evaluations before and after the subconjunctival administrations. CS/HA-EPOβ nanoparticles were administered to the right eye (OD), and the contralateral eye (OS) served as control. At selected timepoints, animals from each group (n = 3) were euthanized, and both eyes were enucleated for histological evaluation (immunofluorescence and HE). No adverse ocular signs, no changes in the microhematocrits (≈45%), and no deviations in the electroretinographies in both photopic and scotopic exams were observed after the administrations (p < 0.05). Intraocular pressure remained in the physiological range during the assays (11–22 mmHg). EPOβ was detected in the retina by immunofluorescence 12 h after the subconjunctival administration and remained detectable until day 21. We concluded that CS/HA nanoparticles could efficiently deliver EPOβ into the retina, and this alternative was considered biologically safe. This nanoformulation could be a promising tool for treating retinopathies, namely optic nerve degeneration associated with glaucoma.
Gender Related Differences in the Clinical Presentation of Hypertrophic Cardiomyopathy—An Analysis from the SILICOFCM Database
Authors: Preveden Andrej , Golubovic Miodrag , Bjelobrk Marija , Miljkovic Tatjana , Ilic Aleksandra , Stojsic Snezana , Gajic Dragan , Glavaski Mila , Maier Lars S. , Okwose Nduka , Popovic Dejana , Barlocco Fausto , Ristic Arsen , MacGowan Guy A. , Olivotto Iacopo , Filipovic Nenad , Jakovljevic Djordje G. , Velicki Lazar
Published: February 2022

Background and Objectives: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease that affects approximately 1 in 500 people. Due to an incomplete disease penetrance associated with numerous factors, HCM is not manifested in all carriers of genetic mutation. Although about two-thirds of patients are male, it seems that female gender is associated with more severe disease phenotype and worse prognosis. The objective of this study was to evaluate the gender related differences in HCM presentation. Materials and Methods: This study was conducted as a part of the international multidisciplinary SILICOFCM project. Clinical information, laboratory analyses, electrocardiography, echocardiography, and genetic testing data were collected for 362 HCM patients from four clinical centers (Florence, Newcastle, Novi Sad, and Regensburg). There were 33% female patients, and 67% male patients. Results: Female patients were older than males (64.5 vs. 53.5 years, p < 0.0005). The male predominance was present across all age groups until the age of 70, when gender distribution became comparable. Females had higher number of symptomatic individuals then males (69% vs. 52%, p = 0.003), most frequently complaining of dyspnea (50% vs. 30%), followed by chest pain (30% vs. 17%), fatigue (26% vs. 13%), palpitations (22% vs. 13%), and syncope (13% vs. 8%). The most common rhythm disorder was atrial fibrillation which was present in a similar number of females and males (19% vs. 13%, p = 0.218). Levels of N-terminal pro-brain natriuretic peptide were comparable between the genders (571 vs. 794 ng/L, p = 0.244). Echocardiography showed similar thickness of interventricular septum (18 vs. 16 mm, p = 0.121) and posterolateral wall (13 vs. 12 mm, p = 0.656), however, females had a lower number of systolic anterior motion (8% vs. 16%, p = 0.020) and other mitral valve abnormalities. Conclusions: Female patients are underrepresented but seem to have a more pronounced clinical presentation of HCM. Therefore, establishing gender specific diagnostic criteria for HCM should be considered.
Understanding the Role of Surface Modification of Randomized Trabecular Titanium Structures in Bone Tissue Regeneration: An Experimental Study
Authors: Canciani Elena , Ragone Vincenza , Biffi Carlo Alberto , Valenza Fabrizio , D’Ambrosi Riccardo , Olimpo Matteo , Cristofalo Aurora , Galliera Emanuela , Dellavia Claudia
Published: February 2022

Background and Objectives: Three-dimensional (3D) metallic trabecular structures made by additive manufacturing (AM) technologies promote new bone formation and osteointegration. Surface modifications by chemical treatments can improve the osteoconductive properties of metallic structures. An in vivo study in sheep was conducted to assess the bone response to randomized trabecular titanium structures that underwent a surface modification by chemical treatment compared to the bone response to the untreated specimens. Material and Methods: Sixteen specimens with a randomized trabecular titanium structure were implanted in the spongious bone of the distal femur and proximal tibia and the cortical bone of the tibial diaphysis of two sheep. Of them, eight implants had undergone a chemical treatment (treated) and were compared to eight implants with the same structure but native surfaces (native). The sheep were sacrificed at 6 weeks. Surface features of the lattice structures (native and treated) were analyzed using a 3D non-contact profilometer. Compression tests of 18 lattice cubes were performed to investigate the mechanical properties of the two structures. Excellent biocompatibility for the trabecular structures was demonstrated in vitro using a cell mouse fibroblast culture. Histomorphometric analysis was performed to evaluate bone implant contact and bone ingrowth. Results: A compression test of lattice cubic specimens revealed a comparable maximum compressive strength value between the two tested groups (5099 N for native surfaces; 5558 N for treated surfaces; p > 0.05). Compared to native surfaces, a homogenous formation of micropores was observed on the surface of most trabeculae that increased the surface roughness of the treated specimens (4.3 versus 3.2 µm). The cellular viability of cells seeded on three-dimensional structure surfaces increased over time compared to that on plastic surfaces. The histomorphometric data revealed a similar behavior and response in spongious and cortical bone formation. The percentage of the implant surface in direct contact with the regenerated bone matrix (BIC) was not significantly different between the two groups either in the spongious bone (BIC: 27% for treated specimens versus 30% for native samples) or in the cortical bone (BIC: 75% for treated specimens versus 77% for native samples). Conclusions: The results of this study reveal rapid osseointegration and excellent biocompatibility for the trabecular structure regardless of surface treatment using AM technologies. The application of implant surfaces can be optimized to achieve a strong press-fit and stability, overcoming the demand for additional chemical surface treatments.
Ferroptosis Involvement in Glioblastoma Treatment
Authors: Mitre Andrei-Otto , Florian Alexandru Ioan , Buruiana Andrei , Boer Armand , Moldovan Ioana , Soritau Olga , Florian Stefan Ioan , Susman Sergiu
Published: February 2022

Glioblastoma multiforme (GBM) is one of the deadliest brain tumors. Current standard therapy includes tumor resection surgery followed by radiotherapy and chemotherapy. Due to the tumors invasive nature, recurrences are almost a certainty, giving the patients after diagnosis only a 12–15 months average survival time. Therefore, there is a dire need of finding new therapies that could potentially improve patient outcomes. Ferroptosis is a newly described form of cell death with several implications in cancer, among which GBM. Agents that target different molecules involved in ferroptosis and that stimulate this process have been described as potentially adjuvant anti-cancer treatment options. In GBM, ferroptosis stimulation inhibits tumor growth, improves patient survival, and increases the efficacy of radiation and chemotherapy. This review provides an overview of the current knowledge regarding ferroptosis modulation in GBM.
Beta-Blocker-Related Atrioventricular Conduction Disorders—A Single Tertiary Referral Center Experience
Authors: Marcu Dragoș Traian Marius , Adam Cristina Andreea , Dorobanțu Dan-Mihai , Șalaru Delia Lidia , Sascău Radu Andy , Balasanian Mircea Ovanez , Macovei Liviu , Arsenescu-Georgescu Cătălina , Stătescu Cristian
Published: February 2022

Background and Objectives: Drug-related bradyarrhythmia is a well-documented major adverse event among beta-blocker users and a potential cause for hospitalization or additional interventions. Whether beta-blocker use is associated with specific bradyarrhythmia presentations, and how this relates to other predisposing factors, is not well known. We aim to evaluate the association between beta-blocker use and the type of atrioventricular (AV) conduction disorder in patients with symptomatic bradycardia. Materials and Methods: We conducted a retrospective cohort study on 596 patients with a primary diagnosis of symptomatic bradyarrhythmia admitted to a single tertiary referral center. Of the cases analyzed, 253 patients were on beta-blocker treatment at presentation and 343 had no bradycardic treatment. We analyzed demographics, clinical and paraclinical parameters in relation to the identified AV conduction disorder. A multivariate regression analysis was performed to explore factors associated with beta-blocker use. Results: Of the 596 patients (mean age 73.9 ± 8.8 years, 49.2% male), 261 (43.8%) had a third-degree AV block, 92 (15.4%) had a second-degree AV block, 128 (21.5%) had slow atrial fibrillation, 93 (15.6%) had sick sinus syndrome and 21 (3.5%) had sinus bradycardia/sinus pauses. Beta-blocker use was associated with the female gender (p < 0.001), emergency admission (p < 0.001), dilated cardiomyopathy (p = 0.003), the lower left ventricular ejection fraction (p = 0.02), mitral stenosis (p = 0.009), chronic kidney disease (p = 0.02), higher potassium levels (p = 0.04) and QRS duration > 120 ms (p = 0.02). Slow atrial fibrillation (OR = 4.2, p < 0.001), sick sinus syndrome (OR = 2.8, p = 0.001) and sinus bradycardia/pauses (OR = 32.9, p < 0.001) were more likely to be associated with beta-blocker use compared to the most common presentation (third-degree AV block), after adjusting for other patient characteristics. Conclusions: Beta-blocker use is more likely to be associated with slow atrial fibrillation, sick sinus syndrome and sinus bradycardia/pauses, compared to a second- or third-degree AV block, after adjusting for other patient factors such as gender, admission type, ECG, comorbidities, cardiac function and lab testing.
Vaccination against Tick-Borne Encephalitis (TBE) in Italy: Still a Long Way to Go
Authors: Panatto Donatella , Domnich Alexander , Amicizia Daniela , Reggio Paolo , Iantomasi Raffaella
Published: February 2022

Tick-borne encephalitis (TBE) is endemic in several European countries, and its incidence has recently increased. Various factors may explain this phenomenon: social factors (changes in human behavior, duration and type of leisure activities and increased tourism in European high-risk areas), ecological factors (e.g., effects of climate change on the tick population and reservoir animals), and technological factors (improved diagnostics, increased medical awareness). Furthermore, the real burden of TBE is not completely known, as the performance of surveillance systems is suboptimal and cases of disease are under-reported in several areas. Given the potentially severe clinical course of the disease, the absence of any antiviral therapy, and the impossibility of interrupting the transmission of the virus in nature, vaccination is the mainstay of prevention and control. TBE vaccines are effective (protective effect of approximately 95% after completion of the basic vaccination—three doses) and well tolerated. However, their uptake in endemic areas is suboptimal. In the main endemic countries where vaccination is included in the national/regional immunization program (with reimbursed vaccination programs), this decision was driven by a cost-effectiveness assessment (CEA), which is a helpful tool in the decision-making process. All CEA studies conducted have demonstrated the cost-effectiveness of TBE vaccination. Unfortunately, CEA is still lacking in many endemic countries, including Italy. In the future, it will be necessary to fill this gap in order to introduce an effective vaccination strategy in endemic areas. Finally, raising awareness of TBE, its consequences and the benefit of vaccination is critical in order to increase vaccination coverage and reduce the burden of the disease.
Genomic Diversity of SARS-CoV-2 in Algeria and North African Countries: What We Know So Far and What We Expect?
Authors: Menasria Taha , Aguilera Margarita
Published: February 2022

Here, we report a first comprehensive genomic analysis of SARS-CoV-2 variants circulating in North African countries, including Algeria, Egypt, Libya, Morocco, Sudan and Tunisia, with respect to genomic clades and mutational patterns. As of December 2021, a total of 1669 high-coverage whole-genome sequences submitted to EpiCoV GISAID database were analyzed to infer clades and mutation annotation compared with the wild-type variant Wuhan-Hu-1. Phylogenetic analysis of SARS-CoV-2 genomes revealed the existence of eleven GISAID clades with GR (variant of the spike protein S-D614G and nucleocapsid protein N-G204R), GH (variant of the ORF3a coding protein ORF3a-Q57H) and GK (variant S-T478K) being the most common with 25.9%, 19.9%, and 19.6%, respectively, followed by their parent clade G (variant S-D614G) (10.3%). Lower prevalence was noted for GRY (variant S-N501Y) (5.1%), S (variant ORF8-L84S) (3.1%) and GV (variant of the ORF3a coding protein NS3-G251V) (2.0%). Interestingly, 1.5% of total genomes were assigned as GRA (Omicron), the newly emerged clade. Across the North African countries, 108 SARS-CoV-2 lineages using the Pangolin assignment were identified, whereby most genomes fell within six major lineages and variants of concern (VOC) including B.1, the Delta variants (AY.X, B.1.617.2), C.36, B.1.1.7 and B.1.1. The effect of mutations in SAR-CoV-2 genomes highlighted similar profiles with D614G spike (S) and ORF1b-P314L variants as the most changes found in 95.3% and 87.9% of total sequences, respectively. In addition, mutations affecting other viral proteins appeared frequently including; N:RG203KR, N:G212V, NSP3:T428I, ORF3a:Q57H, S:N501Y, M:I82T and E:V5F. These findings highlight the importance of genomic surveillance for understanding the SARS-CoV-2 genetic diversity and its spread patterns, leading to a better guiding of public health intervention measures. The know-how analysis of the present work could be implemented worldwide in order to overcome this health crisis through harmonized approaches.
Molecular Epidemiology of Multidrug-Resistant Pneumococci among Ghanaian Children under Five Years Post PCV13 Using MLST
Authors: Mills Richael O. , Abdullah Mohammed R. , Akwetey Samuel A. , Sappor Dorcas C. , Gámez Gustavo , Hammerschmidt Sven
Published: February 2022

Antibiotic resistance in pneumococci contributes to the high pneumococcal deaths in children. We assessed the molecular characteristics of multidrug-resistant (MDR) pneumococci isolated from healthy vaccinated children under five years of age in Cape Coast, Ghana. A total of 43 MDR isolates were selected from 151 pneumococcal strains obtained from nasopharyngeal carriage. All isolates were previously serotyped by multiplex PCR and Quellung reaction. Susceptibility testing was performed using either the E-test or disk diffusion method. Virulence and antibiotic resistance genes were identified by PCR. Molecular epidemiology was analyzed using multilocus sequence typing (MLST). Vaccine-serotypes 23F and 19F were predominant. The lytA and pavB virulence genes were present in all isolates, whiles 14–86% of the isolates carried pilus-islets 1 and 2, pcpA, and psrP genes. Penicillin, tetracycline, and cotrimoxazole resistance were evident in >90% of the isolates. The ermB, mefA, and tetM genes were detected in (n = 7, 16.3%), (n = 4, 9.3%) and (n = 43, 100%) of the isolates, respectively. However, >60% showed alteration in the pbp2b gene. MLST revealed five novel and six known sequence types (STs). ST156 (Spain9V-3) and ST802 were identified as international antibiotic-resistant clones. The emergence of international-MDR clones in Ghana requires continuous monitoring of the pneumococcus through a robust surveillance system.
An Update of the Sanguinarine and Benzophenanthridine Alkaloids’ Biosynthesis and Their Applications
Authors: Laines-Hidalgo José Ignacio , Muñoz-Sánchez José Armando , Loza-Müller Lloyd , Vázquez-Flota Felipe
Published: February 2022

Benzophenanthridines belong to the benzylisoquinolic alkaloids, representing one of the main groups of this class. These alkaloids include over 120 different compounds, mostly in plants from the Fumariaceae, Papaveraceae, and Rutaceae families, which confer chemical protection against pathogens and herbivores. Industrial uses of BZD include the production of environmentally friendly agrochemicals and livestock food supplements. However, although mainly considered toxic compounds, plants bearing them have been used in traditional medicine and their medical applications as antimicrobials, antiprotozoals, and cytotoxic agents have been envisioned. The biosynthetic pathways for some BZD have been established in different species, allowing for the isolation of the genes and enzymes involved. This knowledge has resulted in a better understanding of the process controlling their synthesis and an opening of the gates towards their exploitation by applying modern biotechnological approaches, such as synthetic biology. This review presents the new advances on BDZ biosynthesis and physiological roles. Industrial applications, mainly with pharmacological approaches, are also revised.
Prediction of Monomeric and Dimeric Structures of CYP102A1 Using AlphaFold2 and AlphaFold Multimer and Assessment of Point Mutation Effect on the Efficiency of Intra- and Interprotein Electron Transfer
Authors: Ivanov Yuri D. , Taldaev Amir , Lisitsa Andrey V. , Ponomarenko Elena A. , Archakov Alexander I.
Published: February 2022

The three-dimensional structure of monomers and homodimers of CYP102A1/WT (wild-type) proteins and their A83F and A83I mutant forms was predicted using the AlphaFold2 (AF2) and AlphaFold Multimer (AFMultimer) programs, which were compared with the rate constants of hydroxylation reactions of these enzyme forms to determine the efficiency of intra- and interprotein electron transport in the CYP102A1 hydroxylase system. The electron transfer rate constants (ket), which determine the rate of indole hydroxylation by the CYP102A1 system, were calculated based on the distances (R) between donor-acceptor prosthetic groups (PG) FAD→FMN→HEME of these proteins using factor β, which describes an exponential decay from R the speed of electron transport (ET) according to the tunnelling mechanism. It was shown that the structure of monomers in the homodimer, calculated using the AlpfaFold Multimer program, is in good agreement with the experimental structures of globular domains (HEME-, FMN-, and FAD-domains) in CYP102A1/WT obtained by X-ray structural analysis, and the structure of isolated monomers predicted in AF2 does not coincide with the structure of monomers in the homodimer, although a high level of similarity in individual domains remains. The structures of monomers and homodimers of A83F and A83I mutants were also calculated, and their structures were compared with the wild-type protein. Significant differences in the structure of all isolated monomers with respect to the structures of monomers in homodimers were also found for them, and at the same time, insignificant differences were revealed for all homodimers. Comparative analysis for CYP102A1/WT between the calculated intra- and interprotein distances FAD→FMN→HEME and the rate constants of hydroxylation in these proteins showed that the distance between prosthetic groups both in the monomer and in the dimer allows the implementation of electron transfer between PGs, which is consistent with experimental literature data about kcat. For the mutant form of monomer A83I, an increase in the distance between PGs was obtained, which can restrict electron transportation compared to WT; however, for the dimer of this protein, a decrease in the distance between PGs was observed compared to the WT form, which can lead to an increase in the electron transfer rate constant and, accordingly, kcat. For the monomer and homodimer of the A83F mutant, the calculations showed an increase in the distance between the PGs compared to the WT form, which should have led to a decrease in the electron transfer rate, but at the same time, for the homodimer, the approach of the aromatic group F262 with heme can speed up transportation for this form and, accordingly, the rate of hydroxylation.
Effect of Cholesterol Molecules on Aβ1-42 Wild-Type and Mutants Trimers
Authors: Nguyen Trung Hai , Nguyen Phuong H. , Ngo Son Tung , Derreumaux Philippe
Published: February 2022

Alzheimer’s disease displays aggregates of the amyloid-beta (Aβ) peptide in the brain, and there is increasing evidence that cholesterol may contribute to the pathogenesis of the disease. Though many experimental and theoretical studies have focused on the interactions of Aβ oligomers with membrane models containing cholesterol, an understanding of the effect of free cholesterol on small Aβ42 oligomers is not fully established. To address this question, we report on replica exchange with a solute tempering simulation of an Aβ42 trimer with cholesterol and compare it with a previous replica exchange molecular dynamics simulation. We show that the binding hot spots of cholesterol are rather complex, involving hydrophobic residues L17–F20 and L30–M35 with a non-negligible contribution of loop residues D22–K28 and N-terminus residues. We also examine the effects of cholesterol on the trimers of the disease-causing A21G and disease-protective A2T mutations by molecular dynamics simulations. We show that these two mutations moderately impact cholesterol-binding modes. In our REST2 simulations, we find that cholesterol is rarely inserted into aggregates but rather attached as dimers and trimers at the surface of Aβ42 oligomers. We propose that cholesterol acts as a glue to speed up the formation of larger aggregates; this provides a mechanistic link between cholesterol and Alzheimer’s disease.
BODIPY Conjugates as Functional Compounds for Medical Diagnostics and Treatment
Authors: Antina Elena , Bumagina Natalia , Marfin Yuriy , Guseva Galina , Nikitina Liliya , Sbytov Dmitry , Telegin Felix
Published: February 2022

Fluorescent dyes absorbing and emitting in the visible and near-IR regions are promising for the development of fluorescent probes for labeling and bio-visualization of body cells. The ability to absorb and emit in the long-wavelength region increases the efficiency of recording the spectral signals of the probes due to the higher permeability of the skin layers. Compared to other fluorescent dyes, BODIPYs are attractive due to their excellent photophysical properties–narrow absorption and emission, intense fluorescence, simple signal modulation for the practical applications. As part of conjugates with biomolecules, BODIPY could act as a biomarker, but as therapeutic agent, which allows solving several problems at once-labeling or bioimaging and treatment based on the suppression of pathogenic microflora and cancer cells, which provides a huge potential for practical application of BODIPY conjugates in medicine. The review is devoted to the discussion of the recent, promising directions of BODIPY application in the field of conjugation with biomolecules. The first direction is associated with the development of BODIPY conjugates with drugs, including compounds of platinum, paclitaxel, chlorambucil, isoxazole, capsaicin, etc. The second direction is devoted to the labeling of vitamins, hormones, lipids, and other biomolecules to control the processes of their transport, localization in target cells, and metabolism. Within the framework of the third direction, the problem of obtaining functional optically active materials by conjugating BODIPY with other colored and fluorescent particles, in particular, phthalocyanines, is being solved.
Bioprospecting Plant Growth Promoting Rhizobacteria for Enhancing the Biological Properties and Phytochemical Composition of Medicinally Important Crops
Authors: Rizvi Asfa , Ahmed Bilal , Khan Mohammad Saghir , El-Beltagi Hossam S. , Umar Shahid , Lee Jintae
Published: February 2022

Traditionally, medicinal plants have long been used as a natural therapy. Plant-derived extracts or phytochemicals have been exploited as food additives and for curing many health-related ailments. The secondary metabolites produced by many plants have become an integral part of human health and have strengthened the value of plant extracts as herbal medicines. To fulfil the demand of health care systems, food and pharmaceutical industries, interest in the cultivation of precious medicinal plants to harvest bio-active compounds has increased considerably worldwide. To achieve maximum biomass and yield, growers generally apply chemical fertilizers which have detrimental impacts on the growth, development and phytoconstituents of such therapeutically important plants. Application of beneficial rhizosphere microbiota is an alternative strategy to enhance the production of valuable medicinal plants under both conventional and stressed conditions due to its low cost, environmentally friendly behaviour and non-destructive impact on fertility of soil, plants and human health. The microbiological approach improves plant growth by various direct and indirect mechanisms involving the abatement of various abiotic stresses. Given the negative impacts of fertilizers and multiple benefits of microbiological resources, the role of plant growth promoting rhizobacteria (PGPR) in the production of biomass and their impact on the quality of bio-active compounds (phytochemicals) and mitigation of abiotic stress to herbal plants have been described in this review. The PGPR based enhancement in the herbal products has potential for use as a low cost phytomedicine which can be used to improve health care systems.
Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine
Authors: Correia Maria João , Pimpão António B. , Fernandes Dalila G. F. , Morello Judit , Sequeira Catarina O. , Calado Joaquim , Antunes Alexandra M. M. , Almeida Manuel S. , Branco Patrícia , Monteiro Emília C. , Vicente João B. , Serpa Jacinta , Pereira Sofia A.
Published: February 2022

In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.
Long-Term Potentiodynamic Testing and Tribometric Properties of Amorphous Alloy Coatings under Saline Environment
Authors: Iqbal Amjad , Iqbal Ayesha , Moskal Grzegorz , Yasir Muhammad , Al-Mansour Abdullah , Khan Mohammad , Alam Shamshad , Shahbaz Muhammad , Zia Adeel , Ejaz Ahsan
Published: February 2022

Protective coatings for harsh environments are always welcome, but they must overcome profound challenges, including corrosion and wear resistance. The purpose of this study is to look into the long-term potentiodynamic polarization measurements and dry tribometric behavior of plasma-sprayed amorphous coatings on AISI 1035 mild steel. To investigate the impact of unique active polarization potentials on the electrochemical studies of the iron-based amorphous layer, which compares favorably to AISI 1035 mild steel, the active potential polarization curve and friction coefficient tests were performed. Scanning electron microscopy (SEM) and energy dispersive x-ray (EDX) analyses were used to investigate the coating’s corrosion behavior. Their mechanical (Tribometric tests at higher sliding speeds) and chemical properties (electrochemical potentiodynamic polarization investigations) have also been thoroughly investigated. There is enough validation that these protective coatings can be used in hostile environments. The effects of long-term corrosion for 24 and 48 h were thoroughly examined. Tribometric examinations revealed that amorphous layers are highly resistant under dry conditions, as they offered a very low and stable friction coefficient less than 4 μ with micro Vickers hardness 1140 ± 22.14 HV, which is more than twice as compared to mild steel AISI 1035. The corrosion resistance of coatings in 3.5 wt % NaCl solution displays active transition characteristics of activation, passivation, over passivation, and pitting, as shown by the potentiodynamic polarization curves.
Bond Strength between CAD/CAM PMMA Denture Base Resins and Characterisation Composites
Authors: Pong Mei Ting , Grymak Anastasiia , Waddell John Neil , Choi Joanne Jung Eun
Published: February 2022

Aim: To measure the bond strength between two different CAD/CAM PMMA denture base resins and three different types of gum characterisation composites. Materials and Methods: CAD/CAM single cross-linked (Telio CAD) and double cross-linked (Vivodent CAD) resins were prepared, obtaining a total of 180 bar specimens. Each specimen was prepared according to the manufacturer’s instructions. The specimens were bonded to three different characterisation composites with varying viscosities; Kulzer Pala-creactive (P), Ivoclar SR Nexco (S), Shofu Ceramage (F). All the specimens were then tested using a chevron-notched three-point bond strength test in a universal testing machine to obtain fracture energy release toughness (MPa√m) and bond strength (MPa). The specimens were thermocycled to simulate 6 and 12 months of ageing in vivo. The results were statistically analysed (SPSS). The fractured surfaces of the tested specimens were examined with a scanning electron microscope (SEM) to evaluate the failure modes. Results: Pala-creactive characterisation composites showed the highest overall bond strength (3.49 ± 0.86 MPa) and fracture toughness (1.59 ± 0.34 MPa√m) when bonded to both CAD PMMA denture resins, which were statistically higher than the values obtained when they were bonded to Telio (p < 0.001). The Ceramage composite showed the lowest bond strength (1.05 ± 0.59 MPa) and fracture toughness (0.47 ± 0.4 MPa√m). The dominant mode of failure for all groups was mixed. Conclusion: Single cross-linked PMMA (Telio) showed a higher overall bond strength compared to double cross-linked PMMA when bonded to three different characterisation composites. Telio CAD showed a clear bond strength decrease after 6 and 12 months of artificial ageing, while Vivodent CAD showed a bond strength increase.
Evaluation of Eosinophilic Cationic Protein as a Marker of Alveolar and Cystic Echinococcosis
Authors: Hotz Julian Frederic , Kaczirek Klaus , Stremitzer Stefan , Waneck Fredrik , Auer Herbert , Perkmann Thomas , Kussmann Manuel , Bauer Philipp Karl , Chen Rui-Yang , Kriz Richard , Burgmann Heinz , Ramharter Michael , Lagler Heimo
Published: February 2022

Echinococcosis is a neglected zoonotic disease and a worldwide public health problem caused by infection with the larval stages of taeniid cestodes of the genus Echinococcus. In vitro studies have demonstrated a protoscolecidal effect of eosinophilic cationic protein (ECP), a granule protein of eosinophilic granulocytes, against E. granulosus. Therefore, the main objective of this study was to evaluate ECP as a biomarker in the treatment of alveolar echinococcosis (AE) and cystic echinococcosis (CE). Data were collected retrospectively from the Vienna Echinococcosis Cohort over 7 years until December 2020. Altogether, 32 patients (16 AE and 16 CE) were included. In the selected patients, serum ECP values were compared before and after the beginning of an operative and/or benzimidazole (BMZ) therapy. Mean ECP serum levels before intervention were significantly (p < 0.05) elevated at 34.0 ± 22.9 μg/L in AE patients and at 38.6 ± 19.9 μg/L in CE patients compared to the control group. After the intervention, mean ECP levels decreased significantly (p < 0.05) to 20.4 ± 14.6 μg/L in AE patients and to 22.4 ± 8.3 μg/L in CE patients. Furthermore, ECP showed a significant (p < 0.05) correlation of k = 0.56 with PET–CTI. Based on the significant decrease after operative and/or BMZ treatment and the correlation with clinical markers such as PET–CTI, it is recommended to investigate ECP more intensively as a marker of AE and CE in prospective studies with larger cohorts.
Metabolic Alteration of Trypanosoma cruzi during Differentiation of Epimastigote to Trypomastigote Forms
Authors: De-Simone Salvatore G. , Bourguignon Saulo C. , Gonçalves Priscila S. , Lechuga Guilherme C. , Provance David W.
Published: February 2022

Intracellular parasites such as Trypanosoma cruzi need to acquire valuable carbon sources from the host cell to replicate. Here, we investigated the energetic metabolism of T. cruzi during metacyclogenesis through the determination of enzymatic activities and quantification by HPLC of glycolytic and Krebs cycle short-chain carboxylic acids. Altered concentrations in pyruvate, acetate, succinate, and glycerate were measured during the growth of epimastigote in the complex medium BHI and their differentiation to trypomastigotes in the chemically defined medium, TAU3AAG. These alterations should represent significant differential metabolic modifications utilized by either form to generate energy. This paper is the first work dealing with the intracellular organic acid concentration measurement in T. cruzi parasites. Although it confirms the previous assumption of the importance of carbohydrate metabolism, it yields an essential improvement in T. cruzi metabolism knowledge.
Development of Nanosuspension Formulations Compatible with Inkjet Printing for the Convenient and Precise Dispensing of Poorly Soluble Drugs
Authors: Leung Dennis H.
Published: February 2022

The pharmaceutical industry has been challenged by the increasing number of poorly soluble drug candidates, resulting in significant issues with obtaining sufficient absorption and bioavailability, risk of exposure variability, and difficulties in achieving a safe therapeutic index. Additionally, the rapid and precise dispensing of specific drug dosages is an important aspect that can enable personalized medicines for the patient. Herein, we report on the development of inkjet printing as a method for delivering precise quantities of poorly soluble drug molecules using commercially available equipment. Despite challenges due to low solubility making it difficult to prepare liquid solutions, stable suspensions of drug nanoparticles with the appropriate viscosity were successfully printed and dispensed onto a thin film suitable for delivery. The drug nanoparticles remained intact and could be reconstituted after printing, demonstrating that they remained stable and retained their advantageous particle size. This demonstrates that inkjet printing can be a practical and convenient approach for dispensing poorly soluble drug molecules when formulated as nanosuspensions.
Computability, Notation, and de re Knowledge of Numbers
Authors: Shapiro Stewart , Snyder Eric , Samuels Richard
Published: February 2022

Saul Kripke once noted that there is a tight connection between computation and de re knowledge of whatever the computation acts upon. For example, the Euclidean algorithm can produce knowledge of which number is the greatest common divisor of two numbers. Arguably, algorithms operate directly on syntactic items, such as strings, and on numbers and the like only via how the numbers are represented. So we broach matters of notation. The purpose of this article is to explore the relationship between the notations acceptable for computation, the usual idealizations involved in theories of computability, flowing from Alan Turing’s monumental work, and de re propositional attitudes toward numbers and other mathematical objects.
Supporting Quadric Method for Designing Freeform Mirrors That Generate Prescribed Near-Field Irradiance Distributions
Authors: Doskolovich Leonid L. , Byzov Egor V. , Mingazov Albert A. , Karapetian Gor J. , Smorodin Vitalii I. , Kazanskiy Nikolay L. , Bykov Dmitry A. , Bezus Evgeni A.
Published: February 2022

We consider a version of the supporting quadric method for designing freeform mirrors that generate prescribed irradiance distributions in the near field. The method is derived for a general case of an incident beam with an arbitrary wavefront. As an example, for a practically important special case of a plane incident wavefront, we design a freeform mirror that generates a complex-shaped uniform irradiance distribution in the form of the abbreviation “IPSI” on a zero background. The designed mirror is fabricated and qualitatively investigated in a proof-of-concept optical experiment. The experimental results confirm the correctness of the proposed approach and demonstrate the manufacturability of the mirrors designed using the considered method.