bluuebunny/crossref_metadata_2025 huggingface dataset:
A Concise Review of State Estimation Techniques for Partial Differential Equation Systems
Authors: Yupanqui Tello Ivan Francisco , Vande Wouwer Alain , Coutinho Daniel
Published: December 2021

While state estimation techniques are routinely applied to systems represented by ordinary differential equation (ODE) models, it remains a challenging task to design an observer for a distributed parameter system described by partial differential equations (PDEs). Indeed, PDE systems present a number of unique challenges related to the space-time dependence of the states, and well-established methods for ODE systems do not translate directly. However, the steady progresses in computational power allows executing increasingly sophisticated algorithms, and the field of state estimation for PDE systems has received revived interest in the last decades, also from a theoretical point of view. This paper provides a concise overview of some of the available methods for the design of state observers, or software sensors, for linear and semilinear PDE systems based on both early and late lumping approaches.
Solving an Integral Equation via Fuzzy Triple Controlled Bipolar Metric Spaces
Authors: Mani Gunaseelan , Gnanaprakasam Arul Joseph , Mitrović Zoran D. , Bota Monica-Felicia
Published: December 2021

In this paper, motivated by the recent result of Sezen, we introduce the notion of fuzzy triple controlled bipolar metric space and prove some fixed point results in this framework. Our results generalize and extend some of the well-known results from the literature. We also explore some of the applications of our key results to integral equations.
Rational Approximation Method for Stiff Initial Value Problems
Authors: Karimov Artur , Butusov Denis , Andreev  Valery , Nepomuceno Erivelton G.
Published: December 2021

While purely numerical methods for solving ordinary differential equations (ODE), e.g., Runge–Kutta methods, are easy to implement, solvers that utilize analytical derivations of the right-hand side of the ODE, such as the Taylor series method, outperform them in many cases. Nevertheless, the Taylor series method is not well-suited for stiff problems since it is explicit and not A-stable. In our paper, we present a numerical-analytical method based on the rational approximation of the ODE solution, which is naturally A- and A(α)-stable. We describe the rational approximation method and consider issues of order, stability, and adaptive step control. Finally, through examples, we prove the superior performance of the rational approximation method when solving highly stiff problems, comparing it with the Taylor series and Runge–Kutta methods of the same accuracy order.
Multi-Objective Artificial Bee Colony Algorithm with Minimum Manhattan Distance for Passive Power Filter Optimization Problems
Authors: Yang Nien-Che , Mehmood Danish , Lai Kai-You
Published: December 2021

Passive power filters (PPFs) are most effective in mitigating harmonic pollution from power systems; however, the design of PPFs involves several objectives, which makes them a complex multiple-objective optimization problem. This study proposes a method to achieve an optimal design of PPFs. We have developed a new multi-objective optimization method based on an artificial bee colony (ABC) algorithm with a minimum Manhattan distance. Four different types of PPFs, namely, single-tuned, second-order damped, third-order damped, and C-type damped order filters, and their characteristics were considered in this study. A series of case studies have been presented to prove the efficiency and better performance of the proposed method over previous well-known algorithms.
The Expanded Role of Chitosan in Localized Antimicrobial Therapy
Authors: Hemmingsen Lisa Myrseth , Škalko-Basnet Nataša , Jøraholmen May Wenche
Published: December 2021

Chitosan is one of the most studied natural origin polymers for biomedical applications. This review focuses on the potential of chitosan in localized antimicrobial therapy to address the challenges of current rising antimicrobial resistance. Due to its mucoadhesiveness, chitosan offers the opportunity to prolong the formulation residence time at mucosal sites; its wound healing properties open possibilities to utilize chitosan as wound dressings with multitargeted activities and more. We provide an unbiased overview of the state-of-the-art chitosan-based delivery systems categorized by the administration site, addressing the site-related challenges and evaluating the representative formulations. Specifically, we offer an in-depth analysis of the current challenges of the chitosan-based novel delivery systems for skin and vaginal infections, including its formulations optimizations and limitations. A brief overview of chitosan’s potential in treating ocular, buccal and dental, and nasal infections is included. We close the review with remarks on toxicity issues and remaining challenges and perspectives.
Dysidenin from the Marine Sponge Citronia sp. Affects the Motility and Morphology of Haemonchus contortus Larvae In Vitro
Authors: Ramage Kelsey S. , Taki Aya C. , Lum Kah Yean , Hayes Sasha , Byrne Joseph J. , Wang Tao , Hofmann Andreas , Ekins Merrick G. , White Jonathan M. , Jabbar Abdul , Davis Rohan A. , Gasser Robin B.
Published: December 2021

High-throughput screening of the NatureBank marine extract library (n = 7616) using a phenotypic assay for the parasitic nematode Haemonchus contortus identified an active extract derived from the Australian marine sponge Citronia sp. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from Citronia sp. resulted in the purification of two known hexachlorinated peptides, dysidenin (1) and dysideathiazole (2). Compound 1 inhibited the growth/development of H. contortus larvae and induced multiple phenotypic changes, including a lethal evisceration (Evi) phenotype and/or somatic cell and tissue destruction. This is the first report of anthelmintic activity for these rare and unique polychlorinated peptides.
Frailty and Different Exercise Interventions to Improve Gait Speed in Older Adults after Acute Coronary Syndrome
Authors: Beigienė Aurelija , Petruševičienė Daiva , Barasaitė Vitalija , Kubilius Raimondas , Macijauskienė Jūratė
Published: December 2021

Background and Objectives: The world’s population is rapidly aging, and it is estimated that, by 2050, every sixth person on earth will be older than 65 years. Around 30% of older adults entering cardiac rehabilitation (CR) meet the criteria of frailty. Frailty identification has not been included in the routine evaluation of CR patients yet, and there is a lack of evidence on what training regimen for improving physical performance in frail people is optimal. Therefore, the aim of our study was to determine the prevalence of frailty and to evaluate the effect of two different complementary training programs on the gait speed of older vulnerable and frail patients with acute coronary syndrome and mid-range-to-preserved left ventricular ejection fraction (≥40%) during short-term CR. Materials and Methods: This randomized controlled trial was conducted from January 2020 to September 2021. CR participants (n = 97) with a mean age of 73.1 ± 5.3 years were randomly allocated into three groups: control (CG, n = 32), intervention-1 (IG-1, n = 32) and intervention-2 (IG-2, n = 33). The patients of all three groups attended a usual inpatient CR program, and two intervention groups additionally received different resistance and balance training programs 3 days a week: the IG-1 underwent complementary training with traditional means of physical therapy, while the IG-2 underwent complementary training with mechanical devices. The mean CR duration was 18.9 ± 1.7 days. Frailty was assessed with the Edmonton Frail Scale, and the 5 m walk test was used to evaluate gait speed. Results: Frailty was determined in 37.1% of participants, and 42.3% met the criteria of being vulnerable. After CR, the gait speed of frail and vulnerable patients significantly improved in all three groups (p < 0.05). In the IG-2, slow gait speed was reversed to normal in the overwhelming majority of patients (p < 0.05), while the CG had the greatest proportion of patients who remained to be slow after CR (p < 0.05). Conclusions: A considerable part of patients entering CR are frail or vulnerable; therefore, it is of crucial importance to assess frailty status in all older people. All three CR programs improved gait speed in frail and vulnerable older patients with ischemic heart disease. Complementary resistance and balance training with mechanical devices more effectively reversed slow gait speed to normal during short-term CR.
Unusual Complicated Gastric Ulcers
Authors: Brătucu Mircea Nicolae , Prunoiu Virgiliu-Mihail , Strâmbu Victor , Brătucu Eugen , Răvaş Maria-Manuela , Simion Laurenţiu , Petre Radu
Published: December 2021

We here draw attention to a practical issue: the approach to certain unusual gastric ulcers with haemorrhage- or perforation-induced complications. This category of ulcers, i.e., giant (over 2–3 cm) and multiple ulcers, is rarely encountered. We discuss the circumstances determining the occurrence of such lesions, their diverse aetiology and pathogenesis, their common manifestations, and the severity of their evolution. Some of the lesions are benign (chronic or acute ulcers), whereas others are neoplastic: carcinoma, stromal tumours, and lymphomas. In gastric ulcers, the characteristics of this particular and rare category of lesions strictly places them in the surgical field, requiring primary surgical intention. Conservative treatments are not effective in such cases, and preoperative biopsies are not appropriate for emergency interventions. Whether these unusual ulcers are benign or malign, they need to be surgically removed.
Enhancement of Physical Characteristics of Styrene–Acrylonitrile Nanofiber Membranes Using Various Post-Treatments for Membrane Distillation
Authors: Sallakhniknezhad Reza , Khorsi Manijeh , Niknejad Ali Sallakh , Bazgir Saeed , Kargari Ali , Sazegar Mohsen , Rasouli Mohsen , Chae Soryong
Published: December 2021

Insufficient mechanical strength and wide pore size distribution of nanofibrous membranes are the key hindrances for their concrete applications in membrane distillation. In this work, various post-treatment methods such as dilute solvent welding, vapor welding, and cold-/hot-pressing processes were used to enhance the physical properties of styrene–acrylonitrile (SAN) nanofiber membranes fabricated by the modified electrospinning process. The effects of injection rate of welding solution and a working distance during the welding process with air-assisted spraying on characteristics of SAN nanofiber membranes were investigated. The welding process was made less time-consuming by optimizing system parameters of the electroblowing process to simultaneously exploit residual solvents of fibers and hot solvent vapor to reduce exposure time. As a result, the welded SAN membranes showed considerable enhancement in mechanical robustness and membrane integrity with a negligible reduction in surface hydrophobicity. The hot-pressed SAN membranes obtained the highest mechanical strength and smallest mean pore size. The modified SAN membranes were used for the desalination of synthetic seawater in a direct contact membrane distillation (DCMD). As a result, it was found that the modified SAN membranes performed well (>99.9% removal of salts) for desalination of synthetic seawater (35 g/L NaCl) during 30 h operation without membrane wetting. The cold-/hot-pressing processes were able to improve mechanical strength and boost liquid entry pressure (LEP) of water. In contrast, the welding processes were preferred to increase membrane flexibility and permeation.
Biodegradable Polymeric Membranes for Organic Solvent/Water Pervaporation Applications
Authors: Chang Pao-Yueh , Wang Jane , Li Si-Yu , Suen Shing-Yi
Published: December 2021

Biodegradable polymers are a green alternative to apply as the base membrane materials in versatile processes. In this study, two dense membranes were made from biodegradable PGS (poly(glycerol sebacate)) and APS (poly(1,3-diamino-2-hydroxypropane-co-polyol sebacate)), respectively. The prepared membranes were characterized by FE-SEM, AFM, ATR-FTIR, TGA, DSC, water contact angle, and degree of swelling, in comparison with the PDMS (polydimethylpolysiloxane) membrane. In the pervaporation process for five organic solvent/water systems at 37 °C, both biodegradable membranes exhibited higher separation factors for ethanol/water and acetic acid/water separations, while the PDMS membrane attained better effectiveness in the other three systems. In particular, a positive relationship between the separation factor and the swelling ratio of organic solvent to water (DSo/DSw) was noticed. In spite of their biodegradability, the stability of both PGS and APS membranes was not deteriorated on ethanol/water pervaporation for one month. Furthermore, these two biodegradable membranes were applied in the pervaporation of simulated ABE (acetone-butanol-ethanol) fermentation solution, and the results were comparable with those reported in the literature.
Acetone Sensor Based on FAIMS-MEMS
Authors: Zhang Junna , Lei Cheng , Liang Ting , Liu Ruifang , Zhao Zhujie , Qi Lei , Ghaffar Abdul , Xiong Jijun
Published: December 2021

In this paper, to address the problems of large blood draws, long testing times, and the inability to achieve dynamic detection of invasive testing for diabetes, stemming from the principle that type 1 diabetic patients exhale significantly higher levels of acetone than normal people, a FAIMS-MEMS gas sensor was designed to detect acetone, which utilizes the characteristics of high sensitivity, fast response, and non-invasive operation. It is prepared by MEMS processes, such as photolithography, etching, and sputtering, its specific dimensions are 4000 μm in length, 3000 μm in width and 800 μm in height and the related test system was built to detect acetone gas. The test results show that when acetone below 0.8 ppm is introduced, the voltage value detected by the sensor basically does not change, while when acetone gas exceeds 1.8 ppm, the voltage value detected by the sensor increases significantly. The detection accuracy of the sensor prepared by this method is about 0.02 ppm/mV, and the voltage change can reach 1 V with a response time of 3 s and a recovery time of 4 s when tested under 20 ppm acetone environment; this has good repeatability and stability, and has great prospects in the field of non-invasive detection of type 1 diabetes.
Legionella Occurrence beyond Cooling Towers and Premise Plumbing
Authors: Schwake David Otto , Alum Absar , Abbaszadegan Morteza
Published: December 2021

Legionella is an environmental pathogen that is responsible for respiratory disease and is a common causative agent of water-related outbreaks. Due to their ability to survive in a broad range of environments, transmission of legionellosis is possible from a variety of sources. Unfortunately, a disproportionate amount of research that is devoted to studying the occurrence of Legionella in environmental reservoirs is aimed toward cooling towers and premise plumbing. As confirmed transmission of Legionella has been linked to many other sources, an over-emphasis on the most common sources may be detrimental to increasing understanding of the spread of legionellosis. This review aims to address this issue by cataloguing studies which have examined the occurrence of Legionella in less commonly investigated environments. By summarizing and discussing reports of Legionella in fresh water, ground water, saltwater, and distribution system drinking water, future environmental and public health researchers will have a resource to aid in investigating these pathogens in relevant sources.
Characterization of the Probiotic Potential of Lactic Acid Bacteria Isolated from Kimchi, Yogurt, and Baby Feces in Hong Kong and Their Performance in Soymilk Fermentation
Authors: Wu Haicui , Shum Tim-Fat , Chiou Jiachi
Published: December 2021

Background: There are several potential healthy or nutritional benefits from the use of lactic acid bacteria (LAB) in foods. This study aimed to characterize the LAB isolates from kimchi, yogurt, and baby feces in the Hong Kong area and evaluate their performance in fermented soymilk, which allowed us to assess their potential use in future experiments. Methods: General characteristics including tolerance to acid, NaCl, bile salts and phenol, antimicrobial activity to various pathogens, and adhesive ability to Caco-2 cells were evaluated using 18 LAB in this study. To further demonstrate the influence of such isolates in soymilk fermentation, we measured viability by plating and noting changes in pH, amino acid content, aglyconic isoflavones content and antioxidant capacities in vitro, such as scavenging ability, and iron chelating ability. Results: In this study, various LAB isolates belonging to Lactobacillusrhamnosus, Lactobacillus sakei, Lactiplantibacillus plantarum, andLeuconostocmesenteroides isolated in Hong Kong were evaluated. L. plantarum isolates R7, AC12, and AC14.1, and L. rhamnosus AC1 showed higher tolerance to acid, NaCl, bile salts, and phenol as compared to the other isolates tested. L. plantarum isolates AC12, AC13 and AC14.1, and L. rhamnosus AC1 harbored strong antimicrobial activity. L. plantarum isolates R7, AC12, AC13 and AC14.1, and L. paracasei isolates R6 and R8 showed higher adhesive ability than the other tested isolates. In soymilk, the viable numbers of L. paracasei R5, L. plantarum R7, L. rhamnosus AC1, L. sakei AC2, and Leu. mesenteroides AC5 were much higher than the other tested isolates after 48 h of fermentation. The pH value measuring the lactic acid level in soymilk fermented by L. plantarum AC14.1 was the lowest in comparison to those in soymilk fermented by other isolates. In addition, the levels of free amino acids and isoflavones in the aglycone forms of L. rhamnosus AC1-fermented soymilk were the highest. L. rhamnosus AC1-fermented soymilk also showed the highest antioxidant potential, including DPPH scavenging ability and iron chelating ability. Conclusions: In general, L. plantarum isolates R7 and AC14.1 and L. rhamnosus AC1 exhibited higher tolerance to challenging conditions as compared to the other isolates. Moreover, L. rhamnosus AC1 exhibited superior performance in soymilk fermentation and potential as a starter and probiotic culture.
Lacticaseibacillus casei ATCC 393 Cannot Colonize the Gastrointestinal Tract of Crucian Carp
Authors: Zhang Hongyu , Mu Xiyan , Wang Hongwei , Wang Haibo , Wang Hui , Li Yingren , Mu Yingchun , Song Jinlong , Xia Lei
Published: December 2021

Lactic acid bacteria (LAB) are commonly applied to fish as a means of growth promotion and disease prevention. However, evidence regarding whether LAB colonize the gastrointestinal (GI) tract of fish remains sparse and controversial. Here, we investigated whether Lacticaseibacillus casei ATCC 393 (Lc) can colonize the GI tract of crucian carp. Sterile feed irradiated with 60Co was used to eliminate the influence of microbes, and 100% rearing water was renewed at 5-day intervals to reduce the fecal–oral circulation of microbes. The experiment lasted 47 days and was divided into three stages: the baseline period (21 days), the administration period (7 days: day −6 to 0) and the post-administration period (day 1 to 19). Control groups were fed a sterile basal diet during the whole experimental period, whereas treatment groups were fed with a mixed diet containing Lc (1 × 107 cfu/g) and spore of Geobacillus stearothermophilus (Gs, 1 × 107 cfu/g) during the administration period and a sterile basal diet during the baseline and post-administration periods. An improved and highly sensitive selective culture method (SCM) was employed in combination with a transit marker (a Gs spore) to monitor the elimination of Lc in the GI tract. The results showed that Lc (<2 cfu/gastrointestine) could not be detected in any of the fish sampled from the treatment group 7 days after the cessation of the mixed diet, whereas Gs could still be detected in seven out of nine fish at day 11 and could not be detected at all at day 15. Therefore, the elimination speed of Lc was faster than that of the transit marker. Furthermore, high-throughput sequencing analysis combined with SCM was used to reconfirm the elimination kinetics of Lc in the GI tract. The results show that the Lc in the crucian carp GI tract, despite being retained at low relative abundance from day 7 (0.11% ± 0.03%) to 21, was not viable. The experiments indicate that Lc ATCC 393 cannot colonize the GI tract of crucian carp, and the improved selective culture in combination with a transit marker represents a good method for studying LAB colonization of fish.
Reduced Susceptibility and Increased Resistance of Bacteria against Disinfectants: A Systematic Review
Authors: Rozman Urška , Pušnik Marko , Kmetec Sergej , Duh Darja , Šostar Turk Sonja
Published: December 2021

Disinfectants are used to reduce the concentration of pathogenic microorganisms to a safe level and help to prevent the transmission of infectious diseases. However, bacteria have a tremendous ability to respond to chemical stress caused by biocides, where overuse and improper use of disinfectants can be reflected in a reduced susceptibility of microorganisms. This review aims to describe whether mutations and thus decreased susceptibility to disinfectants occur in bacteria during disinfectant exposure. A systematic literature review following PRISMA guidelines was conducted with the databases PubMed, Science Direct and Web of Science. For the final analysis, 28 sources that remained of interest were included. Articles describing reduced susceptibility or the resistance of bacteria against seven different disinfectants were identified. The important deviation of the minimum inhibitory concentration was observed in multiple studies for disinfectants based on triclosan and chlorhexidine. A reduced susceptibility to disinfectants and potentially related problems with antibiotic resistance in clinically important bacterial strains are increasing. Since the use of disinfectants in the community is rising, it is clear that reasonable use of available and effective disinfectants is needed. It is necessary to develop and adopt strategies to control disinfectant resistance.
Pulmonary and Extrapulmonary Manifestations in Hospitalized Children with Mycoplasma Pneumoniae Infection
Authors: Biagi Carlotta , Cavallo Alessandra , Rocca Alessandro , Pierantoni Luca , Antonazzo Davide , Dondi Arianna , Gabrielli Liliana , Lazzarotto Tiziana , Lanari Marcello
Published: December 2021

Mycoplasma pneumoniae (MP) is one of the main causes of both upper and lower respiratory infections in school-aged children, accounting for up to 40% of community-acquired pneumonia. Younger children are also affected, and extrapulmonary manifestations have been recently reported in the pediatric population. We carried out a retrospective analysis of MP-positive patients admitted to the Pediatric Emergency Unit of S. Orsola Malpighi University Hospital in Bologna, the largest tertiary pediatric referral center in the Emilia–Romagna region, Northern Italy, between 2012 and 2020. We identified 145 patients with MP infection (82 males and 63 females), 27% of which were younger than 2 years; the median age was 5 years (interquartile range 1–9). The clinical presentation partially differed between age groups. School-aged children were more likely to have a chest X-ray-confirmed pneumonia (p = 0.013), while younger children required oxygen therapy more often (p = 0.048). Seventy-four children (51%) showed extrapulmonary manifestations, mainly gastrointestinal (30%) and dermatological (14%). Neurological symptoms were more frequent in children older than 6 years (p = 0.006). The rate of other extrapulmonary manifestations did not differ significantly between age groups. This study shows that MP infection is a frequent cause of pediatric hospitalization, including of children younger than 2 years. Clinicians should be aware of the variable clinical expressions of MP, including extrapulmonary manifestations, to achieve a correct diagnosis and determine appropriate treatment.
Steroid Metabolism in Thermophilic Actinobacterium Saccharopolyspora hirsuta VKM Ac-666T
Authors: Lobastova Tatyana , Fokina Victoria , Tarlachkov Sergey , Shutov Andrey , Bragin Eugeny , Kazantsev Alexey , Donova Marina
Published: December 2021

The application of thermophilic microorganisms opens new prospects in steroid biotechnology, but little is known to date on steroid catabolism by thermophilic strains. The thermophilic strain Saccharopolyspora hirsuta VKM Ac-666T has been shown to convert various steroids and to fully degrade cholesterol. Cholest-4-en-3-one, cholesta-1,4-dien-3-one, 26-hydroxycholest-4-en-3-one, 3-oxo-cholest-4-en-26-oic acid, 3-oxo-cholesta-1,4-dien-26-oic acid, 26-hydroxycholesterol, 3β-hydroxy-cholest-5-en-26-oic acid were identified as intermediates in cholesterol oxidation. The structures were confirmed by 1H and 13C-NMR analyses. Aliphatic side chain hydroxylation at C26 and the A-ring modification at C3, which are putatively catalyzed by cytochrome P450 monooxygenase CYP125 and cholesterol oxidase, respectively, occur simultaneously in the strain and are followed by cascade reactions of aliphatic sidechain degradation and steroid core destruction via the known 9(10)-seco-pathway. The genes putatively related to the sterol and bile acid degradation pathways form three major clusters in the S. hirsuta genome. The sets of the genes include the orthologs of those involved in steroid catabolism in Mycobacterium tuberculosis H37Rv and Rhodococcus jostii RHA1 and related actinobacteria. Bioinformatics analysis of 52 publicly available genomes of thermophilic bacteria revealed only seven candidate strains that possess the key genes related to the 9(10)-seco pathway of steroid degradation, thus demonstrating that the ability to degrade steroids is not widespread among thermophilic bacteria.
Isolation and Identification of Bacteria with Surface and Antibacterial Activity from the Gut of Mediterranean Grey Mullets
Authors: Floris Rosanna , Sanna Gabriele , Mura Laura , Fiori Myriam , Culurgioni Jacopo , Diciotti Riccardo , Rizzo Carmen , Lo Giudice Angelina , Laganà Pasqualina , Fois Nicola
Published: December 2021

Fish gut represents a peculiar ecological niche where bacteria can transit and reside to play vital roles by producing bio-compounds with nutritional, immunomodulatory and other functions. This complex microbial ecosystem reflects several factors (environment, feeding regimen, fish species, etc.). The objective of the present study was the identification of intestinal microbial strains able to produce molecules called biosurfactants (BSs), which were tested for surface and antibacterial activity in order to select a group of probiotic bacteria for aquaculture use. Forty-two bacterial isolates from the digestive tracts of twenty Mediterranean grey mullets were screened for testing emulsifying (E-24), surface and antibiotic activities. Fifty percent of bacteria, ascribed to Pseudomonas aeruginosa, Pseudomonas sp., P. putida and P. anguilliseptica, P. stutzeri, P. protegens and Enterobacter ludwigii were found to be surfactant producers. Of the tested strains, 26.6% exhibited an antibacterial activity against Staphylococcus aureus (10.0 ± 0.0–14.5 ± 0.7 mm inhibition zone), and among them, 23.3% of isolates also showed inhibitory activity vs. Proteus mirabilis (10.0 ± 0.0–18.5 ± 0.7 mm inhibition zone) and 6.6% vs. Klebsiella pneumoniae (11.5 ± 0.7–17.5 ± 0.7 mm inhibition zone). According to preliminary chemical analysis, the bioactive compounds are suggested to be ascribed to the class of glycolipids. This works indicated that fish gut is a source of bioactive compounds which deserves to be explored.
Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment
Authors: Elzupir Amin Osman
Published: December 2021

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.
An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide
Authors: Holley Claire K. , Cedrone Edward , Donohue Duncan , Neun Barry W. , Verthelyi Daniela , Pang Eric S. , Dobrovolskaia Marina A.
Published: December 2021

Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product’s distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo™ (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay.
New Supramolecular Drug Carriers: The Study of Organogel Conjugated Gold Nanoparticles
Authors: Kowalczuk Joanna , Łapiński Andrzej , Stolarczyk Elżbieta , Demchuk Oleg M. , Kubiński Konrad , Janeczko Monika , Martyna Aleksandra , Masłyk Maciej , Turczyniak-Surdacka Sylwia
Published: December 2021

An aqueous solution of sodium citrate stabilized gold nanoparticles (AuNP) in the presence of N-lauroyl-L-alanine (C12ALA) forms a stable gel. The structure of the gel and the distribution profile of AuNP in it were analyzed. Will nanoparticles separated from each other with sodium citrate behave in the same way in solution and trapped in the gel matrix? Will the spatial limitation of solvent molecules aggregate nanoparticles and destroy their homogeneity? These questions are very important from the point of view of the use of gold nanoparticles, trapped in the gel structure as carriers of drugs in the slow-release process. The lack of homogeneity of this distribution will have a major impact on the rate of release of the appropriate amount of therapeutic drug from the matrix. In this work, we attempt to answer these questions. The performed biological assays revealed that both C12ALA and C12ALA-AuNP show an excellent level of biological neutrality. They might be used as a transporting medium for a drug delivery without affecting the drug’s activity.
Emerging Therapeutic Agents for Colorectal Cancer
Authors: Nalli Marianna , Puxeddu Michela , La Regina Giuseppe , Gianni Stefano , Silvestri Romano
Published: December 2021

There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.
Antioxidant Potential of Flower Extracts from Centaurea spp. Depends on Their Content of Phenolics, Flavonoids and Free Amino Acids
Authors: Salachna Piotr , Pietrak Anna , Łopusiewicz Łukasz
Published: December 2021

Scientists intensely search for new sources of antioxidants, perceived as important health-promoting agents. Some species of the large genus Centaurea provide raw materials for the pharmaceutical and cosmetic industries, as well as produce edible flowers. This is the first study that determines the content of total polyphenols, flavonoids, reducing sugars, free amino acids and the antioxidant potential in the flower extracts of C. nigra L., C. orientalis L. and C. phrygia L. The total polyphenol and flavonoid content is the highest in the extract of C. orientalis, and the lowest in that of C. phrygia. Similarly, C. orientalis shows the greatest scavenging activity on DPPH (1,1-diphenyl-2-picryl-hydrazyl), ABTS [2,2′-azobis(3-ethylbenzothiazoline-6-sulfonate)] and Fe3+ reducing power assays, whereas the lowest activity is found for C. phrygia. The highest content of reducing sugars is found in C. nigra, while C. orientalis has the highest levels of free amino acids. We find a strong positive correlation between total phenolics and flavonoids and the antioxidant capacity of all three Centaurea species. Moreover, the content of free amino acids strongly and positively correlates with the levels of total phenolics and flavonoids, antioxidant activity assessed by DPPH and ABTS assays and Fe3+ reducing power. Summing up, C. orientalis exhibits the strongest antioxidant potential of the investigated Centaurea species. This species could potentially be a natural source of antioxidant substances for the pharmacy, cosmetics and food industries. The content of free amino acids may be used as a marker of the antioxidant status of Centaurea species.
Enhancing Oil Recovery from Low-Permeability Reservoirs with a Thermoviscosifying Water-Soluble Polymer
Authors: Zhang Xiaoqin , Li Bo , Pan Feng , Su Xin , Feng Yujun
Published: December 2021

Water-soluble polymers, mainly partially hydrolyzed polyacrylamide (HPAM), have been used in the enhanced oil recovery (EOR) process. However, the poor salt tolerance, weak thermal stability and unsatisfactory injectivity impede its use in low-permeability hostile oil reservoirs. Here, we examined the adaptivity of a thermoviscosifying polymer (TVP) in comparison with HPAM for chemical EOR under simulated conditions (45 °C, 4500 mg/L salinity containing 65 mg/L Ca2+ and Mg2+) of low-permeability oil reservoirs in Daqing Oilfield. The results show that the viscosity of the 0.1% TVP solution can reach 48 mPa·s, six times that of HPAM. After 90 days of thermal aging at 45 °C, the TVP solution had 71% viscosity retention, 18% higher than that of the HPAM solution. While both polymer solutions could smoothly propagate in porous media, with permeability of around 100 milliDarcy, TVP exhibited stronger mobility reduction and permeability reduction than HPAM. After 0.7 pore volume of 0.1% polymer solution was injected, TVP achieved an incremental oil recovery factor of 13.64% after water flooding, 3.54% higher than that of HPAM under identical conditions. All these results demonstrate that TVP has great potential to be used in low-permeability oil reservoirs for chemical EOR.
Mipsagargin: The Beginning—Not the End—of Thapsigargin Prodrug-Based Cancer Therapeutics
Authors: Isaacs John T. , Brennen William Nathaniel , Christensen Søren Brøgger , Denmeade Samuel R.
Published: December 2021

Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC50~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50–100 nM TG is sustained for >24–48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca2+, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5–8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.
The Discovery of New Drug-Target Interactions for Breast Cancer Treatment
Authors: Song Jiali , Xu Zhenyi , Cao Lei , Wang Meng , Hou Yan , Li Kang
Published: December 2021

Drug–target interaction (DTIs) prediction plays a vital role in probing new targets for breast cancer research. Considering the multifaceted challenges associated with experimental methods identifying DTIs, the in silico prediction of such interactions merits exploration. In this study, we develop a feature-based method to infer unknown DTIs, called PsePDC-DTIs, which fuses information regarding protein sequences extracted by pseudo-position specific scoring matrix (PsePSSM), detrended cross-correlation analysis coefficient (DCCA coefficient), and an FP2 format molecular fingerprint descriptor of drug compounds. In addition, the synthetic minority oversampling technique (SMOTE) is employed for dealing with the imbalanced data after Lasso dimensionality reduction. Then, the processed feature vectors are put into a random forest classifier to perform DTIs predictions on four gold standard datasets, including nuclear receptors (NR), G-protein-coupled receptors (GPCR), ion channels (IC), and enzymes (E). Furthermore, we explore new targets for breast cancer treatment using its risk genes identified from large-scale genome-wide genetic studies using PsePDC-DTIs. Through five-fold cross-validation, the average values of accuracy in NR, GPCR, IC, and E datasets are 95.28%, 96.19%, 96.74%, and 98.22%, respectively. The PsePDC-DTIs model provides us with 10 potential DTIs for breast cancer treatment, among which erlotinib (DB00530) and FGFR2 (hsa2263), caffeine (DB00201) and KCNN4 (hsa3783), as well as afatinib (DB08916) and FGFR2 (hsa2263) are found with direct or inferred evidence. The PsePDC-DTIs model has achieved good prediction results, establishing the validity and superiority of the proposed method.
Genetic Modification Approaches for Parasporins Bacillus thuringiensis Proteins with Anticancer Activity
Authors: Suárez-Barrera Miguel O. , Visser Lydia , Rondón-Villarreal Paola , Herrera-Pineda Diego F. , Alarcón-Aldana Juan S. , Van den Berg Anke , Orozco Jahir , Pinzón-Reyes Efraín H. , Moreno Ernesto , Rueda-Forero Nohora J.
Published: December 2021

Bacillus thuringiensis (Bt) is a bacterium capable of producing Cry toxins, which are recognized for their bio-controlling actions against insects. However, a few Bt strains encode proteins lacking insecticidal activity but showing cytotoxic activity against different cancer cell lines and low or no cytotoxicity toward normal human cells. A subset of Cry anticancer proteins, termed parasporins (PSs), has recently arisen as a potential alternative for cancer treatment. However, the molecular receptors that allow the binding of PSs to cells and their cytotoxic mechanisms of action have not been well established. Nonetheless, their selective cytotoxic activity against different types of cancer cell lines places PSs as a promising alternative treatment modality. In this review, we provide an overview of the classification, structures, mechanisms of action, and insights obtained from genetic modification approaches for PS proteins.
Bioactive Pectin-Murta (Ugni molinae T.) Seed Extract Films Reinforced with Chitin Fibers
Authors: Cabrera-Barjas Gustavo , Nesic Aleksandra , Bravo-Arrepol Gaston , Rodríguez-Llamazares Saddys , Valdés Oscar , Banerjee Aparna , Castaño Johanna , Delattre Cédric
Published: December 2021

This study investigated the biocomposite pectin films enriched with murta (Ugni molinae T.) seed polyphenolic extract and reinforced by chitin nanofiber. The structural, morphological, mechanical, barrier, colorimetric, and antioxidant activity of films were evaluated. The obtained data clearly demonstrated that the addition of murta seed extract and the high load of chitin nanofibers (50%) provided more cohesive and dense morphology of films and improved the mechanical resistance and water vapor barrier in comparison to the control pectin film. The antioxidant activity ranged between 71% and 86%, depending on the film formulation and concentration of chitin nanofibers. The presented results highlight the potential use of chitin nanofibers and murta seed extract in the pectin matrix to be applied in functional food coatings and packaging, as a sustainable solution.
Ionic Liquid Extraction Behavior of Cr(VI) Absorbed on Humic Acid–Vermiculite
Authors: Huang Hsin-Liang , Lin P.C. , Wang H.T. , Huang Hsin-Hung , Wu Chao-Ho
Published: December 2021

Cr(VI) can be released into soil as a result of mining, electroplating, and smelting operations. Due to the high toxicity of Cr(VI), its removal is necessary in order to protect ecosystems. Vermiculite is applied in situations where there is a high degree of metal pollution, as it is helpful during the remediation process due to its high cation exchange capacity. The Cr(VI) contained in the vermiculite should be extracted in order to recover it and to reduce the impact on the environment. In this work, adsorption equilibrium data for Cr(VI) in a simulated sorbent for soil remediation (a mixture that included both humic acid (HA) and vermiculite) were a good fit with the Langmuir isotherm model. The simulated sorbent for soil remediation was a favorable sorbent for Cr(VI) when it was in the test soil. An ionic liquid, [C4mim]Cl (1-butyl-3-methylimidazolium chloride), was studied to determine its efficiency in extracting Cr(VI) from the Cr- contaminated simulated sorbent in soil remediation. At 298 K and within 30 min, approximately 33.48 ± 0.79% of Cr(VI) in the simulated sorbent in soil remediation was extracted into [C4mim]Cl. Using FTIR spectroscopy, the absorbance intensities of the bands at 1032 and 1010 cm−1, which were attributed to C-O bond stretching in the polysaccharides of HA, were used to detect the changes in HA in the Cr-contaminated simulated sorbent for soil remediation before and after extraction. The results showed that Cr(VI) that has been absorbed on HA can be extracted into [C4mim]Cl. Using 1H NMR, it was observed that the 1-methylimizadole of [C4mim] Cl played an important role in the extraction of Cr(VI), which bonded with HA on vermiculite and was able to be transformed into the [C4mim]Cl phase.
DFT-D4 Insight into the Inclusion of Amphetamine and Methamphetamine in Cucurbit[7]uril: Energetic, Structural and Biosensing Properties
Authors: Litim Abdelkarim , Belhocine Youghourta , Benlecheb Tahar , Ghoniem Monira Galal , Kabouche Zoubir , Ali Fatima Adam Mohamed , Abdulkhair Babiker Yagoub , Seydou Mahamadou , Rahali Seyfeddine
Published: December 2021

The host–guest interactions of cucurbit[7]uril (CB[7]) as host and amphetamine (AMP), methamphetamine (MET) and their enantiomeric forms (S-form and R-form) as guests were computationally investigated using density functional theory calculations with the recent D4 atomic-charge dependent dispersion corrections. The analysis of energetic, structural and electronic properties with the aid of frontier molecular orbital analysis, charge decomposition analysis (CDA), extended charge decomposition analysis (ECDA) and independent gradient model (IGM) approach allowed to characterize the host–guest interactions in the studied systems. Energetic results indicate the formation of stable non-covalent complexes where R-AMP@CB[7] and S-AMP@CB[7] are more stable thermodynamically than R-MET@CB[7] and S-MET@CB[7] in gas phase while the reverse is true in water solvent. Based on structural analysis, a recognition mechanism is proposed, which suggests that the synergistic effect of van der Waals forces, ion–dipole interactions, intermolecular charge transfer interactions and intermolecular hydrogen bonding is responsible for the stabilization of the complexes. The geometries of the complexes obtained theoretically are in good agreement with the X-ray experimental structures and indicate that the phenyl ring of amphetamine and methamphetamine is deeply buried into the cavity of CB[7] through hydrophobic interactions while the ammonium group remains outside the cavity to establish hydrogen bonds with the portal oxygen atoms of CB[7].