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Coxsackievirus B (CVB) infections, ranging from mild to severe diseases, lack specific antiviral treatments, underscoring the need for novel therapeutic strategies. Drug therapy is an important tool for controlling enterovirus infections, but clinically effective drugs do not currently exist, mainly due to the development of drug resistance. Combination therapy with two or more drugs has the potential to successfully inhibit viral infection more effectively than either drug alone as well as delay the development of resistance. This study explores the consecutive alternating administration (CAA) scheme in mice with CVB1 infection, utilizing double antiviral combinations consisting of pleconaril and MDL-860, with guanidine hydrochloride and oxoglaucine. The CAA combinations of pleconaril achieved a survival rate, in infected mice, of up to 59%, while the combinations of MDL-860 showed no significant effects. CAA reduced mortality, prolonged mean survival time (up to 5 days), and mitigated drug resistance compared to monotherapy or simultaneous administration. Monotherapeutic courses and daily administration of double combinations had no effect. Phenotypic characterization using the IC50 marker of virus isolates from brain tissue of infected and treated mice was of particular importance for the evaluation of the CAA treatment scheme. The results show increased susceptibility of the virus isolates to the partner compounds in double CAA combinations. In contrast, virus isolates from the monotherapeutic groups manifested a diminished susceptibility to their respective compound, which signals the development of drug resistance. All data obtained prove the potential of the CAA scheme for the development of effective chemotherapy of enterovirus infections.

This review describes the enhanced classification of polyphenols into flavonoids, lignans, phenolic acids, stilbenes, and tannins. Its focus is the natural sources of polyphenols and an in-depth discussion of their antibacterial, antifungal, and antiviral activity. Besides a broad literature overview, this paper contains authors’ experimental data according to some daily consumed vegetables such as tomatoes, different varieties of onion, garlic, parsley, and cayenne pepper and the probable relation of these activities to polyphenols. The isolation of polyphenols via conventional and ultrasonic, pressurized liquids and pulse-field extractions, as well as their methods for detection and determination, are interpreted as well. The main mechanisms by which polyphenols inhibit the growth of bacteria, fungi, and viruses, such as protein synthesis, cell membrane destabilization, and ROS production induction, are in focus. Data on polyphenol concentrations and their respective MIC or the inhibition zone diameters of different bacterial and fungal species and suppressing viral replication are depicted. The toxicity of polyphenols in vitro, ex vivo, and in vivo towards microorganisms and human/animal cells, and the safety of the polyphenols applied in clinical and industrial applications are expanded. This review also characterizes the antimicrobial effects of some chemically synthesized polyphenol derivatives. Biotechnological advances are also reported, especially the entrapment of polyphenols in biocompatible nanoparticles to enhance their bioavailability and efficacy. Polyphenols are promising for exploring molecules’ novel antimicrobial substances and paving the path for effective novel antimicrobial agents’ discovery, taking into consideration their positives and negatives.

The challenges in combating enteroviruses continue due to their genetic diversity and the rapid development of resistance. Combining antiviral agents offers a promising solution. Our study evaluated the combined effects of pocapavir, a potent capsid-binding inhibitor, with enterovirus-targeting compounds such as pleconaril, 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860), guanidine hydrochloride, oxoglaucine, and 2-α-hydroxybenzyl-benzimidazole (HBB). The combinations tested demonstrated additive to highly synergistic antiviral effects without observed combined cytotoxicity. These results suggest their potential for further research and clinical trials in combating enterovirus infections.

Coxsackievirus B (CVB) infections, ranging from mild to severe diseases, lack specific antiviral treatments, underscoring the need for novel therapeutic strategies. Drug therapy is an important tool for controlling enterovirus infections, but clinically effective drugs do not currently exist, mainly due to the development of drug resistance. Combination therapy with two or more drugs has the potential to successfully inhibit viral infection more effectively than either drug alone as well as delay the development of resistance. This study explores the consecutive alternating administration (CAA) scheme in mice with CVB1 infection, utilizing double antiviral combinations consisting of pleconaril and MDL-860, with guanidine hydrochloride and oxoglaucine. The CAA combinations of pleconaril achieved a survival rate, in infected mice, of up to 59%, while the combinations of MDL-860 showed no significant effects. CAA reduced mortality, prolonged mean survival time (up to 5 days), and mitigated drug resistance compared to monotherapy or simultaneous administration. Monotherapeutic courses and daily administration of double combinations had no effect. Phenotypic characterization using the IC50 marker of virus isolates from brain tissue of infected and treated mice was of particular importance for the evaluation of the CAA treatment scheme. The results show increased susceptibility of the virus isolates to the partner compounds in double CAA combinations. In contrast, virus isolates from the monotherapeutic groups manifested a diminished susceptibility to their respective compound, which signals the development of drug resistance. All data obtained prove the potential of the CAA scheme for the development of effective chemotherapy of enterovirus infections. [ABSTRACT FROM AUTHOR]

Microfluidics, also known as lab-on-a-chip or micro total analysis systems, can precisely regulate and manipulate micro-sized fluids. They have great potential in biology, chemistry, and medicine, as well as other fields of science. By definition, microfluidic devices operate with small-volume samples and small reactant quantities, which renders them both efficient and affordable. However, such small objects have very demanding requirements for the utilized optical detection system. Due to the specifics of those devices, monitoring the results of experiments is carried out with commercial inverted optical microscopes. Unfortunately, that type of optical device is still expensive. In this article, we present a truly functional, inexpensive, standalone, three-dimensionally printed, and inverted microscope, including the design, engineering, and manufacturing process and some of the experiments that have been conducted with it. Finally, we summarize the advantages of this three-dimensionally printed microscope (including the total fabrication costs) and the future improvements that will be introduced to it.

The paper purpose is to propose an approach to the analysis of the impact of various natural disasters (intense rainfall, extreme high or low temperatures, droughts, strong storms, floods, earthquakes and others) on the economic efficiency and profitability of the business. In this study, more specifically, the business companies in the sphere of production, trade and services are considered. These companies generate net income from sales of production, goods and services. In view of the successful development and sustainability of these companies, it is necessary to analyse the variations in specific ratios of two of the main business indicators (economic efficiency and profitability) under the influence of different natural disasters. The ratios related to the indicator of economic efficiency and profitability are calculated as the corresponding net revenues or profits from sales (of production, goods and services) are divided by one of the following variables: sum of the average balance values of current or fixed tangible assets, incurred full costs of the activity or other. Numerical results of several applications of the proposed approach with particular values of the variables that are included in the expressions describing the two business indicators are presented. The results of the analysis of the calculated values of the ratios related to the two business indicators (economic efficiency and profitability) before and after the possible occurrence of a given natural disaster can successfully support decision-making financial managers to take adequate measures to reduce the potential negative consequences, recover the normal operative activity or increasing resilience of companies.

AbstractCoxsackieviruses are distributed worldwide and can cause serious diseases threatening human health and even human life. Genetic silencing is considered a new opportunity to treat viral infections. In this study, we produced in vitro dsRNAs and siRNAs specific for two sequences of different length from the VP1 genetic regions of CVB3, and introduced them into HEp-2 cells with Oligofectamine as the transfection agent. We used the neurotropic strain Nancy. The 100% inhibitory concentrations of the applied dsRNAs and siRNAs were 0.3 μmol/L and fell in the range of non-cytotoxic concentration values. The produced VP1-specific dsRNAs and siRNAs were effective at low concentrations, suggesting that the produced RNAs are safe to use and possess excellent potential to treat CVB3 infection.

This review describes the enhanced classification of polyphenols into flavonoids, lignans, phenolic acids, stilbenes, and tannins. Its focus is the natural sources of polyphenols and an in-depth discussion of their antibacterial, antifungal, and antiviral activity. Besides a broad literature overview, this paper contains authors' experimental data according to some daily consumed vegetables such as tomatoes, different varieties of onion, garlic, parsley, and cayenne pepper and the probable relation of these activities to polyphenols. The isolation of polyphenols via conventional and ultrasonic, pressurized liquids and pulse-field extractions, as well as their methods for detection and determination, are interpreted as well. The main mechanisms by which polyphenols inhibit the growth of bacteria, fungi, and viruses, such as protein synthesis, cell membrane destabilization, and ROS production induction, are in focus. Data on polyphenol concentrations and their respective MIC or the inhibition zone diameters of different bacterial and fungal species and suppressing viral replication are depicted. The toxicity of polyphenols in vitro, ex vivo, and in vivo towards microorganisms and human/animal cells, and the safety of the polyphenols applied in clinical and industrial applications are expanded. This review also characterizes the antimicrobial effects of some chemically synthesized polyphenol derivatives. Biotechnological advances are also reported, especially the entrapment of polyphenols in biocompatible nanoparticles to enhance their bioavailability and efficacy. Polyphenols are promising for exploring molecules' novel antimicrobial substances and paving the path for effective novel antimicrobial agents' discovery, taking into consideration their positives and negatives. [ABSTRACT FROM AUTHOR]

Introduction.The generation of polynomial power laws of motion for the synthesis of cam mechanisms is complicated by the need to determine the coefficients of power polynomials. The study objective is to discover a rational capability of generating рower law swith arbitrary terms number under s with an rbitrary number of terms under the synthesis of cam mechanisms.Materials and Methods.A unified formula for determining the values of coefficients of power polynomials with any number of integers and/or non-integer exponents is derived through the so-called transfinite mathematical induction. Results.A unified formula for determining the values of coefficients, which gives correct results for any number of even and/or odd exponents, is presented. The correctness of the derived formula is validated by the results on the multiple checks for different numbers, even and odd values of the exponents of quinquinomial and hexanomial power functions. Discussion and Conclusions. A unified formula for determining the values of coefficients of power polynomials makes it possible to rationally define the laws of motion without finite and infinite spikes in the synthesis of elastic cam-lever systems. This provides a rational determination of the laws of motion without finite and infinite spikes in the synthesis of elastic cam-lever systems, and simple verification of the accuracy of the results obtained. The functions are particularly suitable for the synthesis of polydyne cams, as well as cams, since one polynomial can be used throughout the entire geometric mechanism cycle.

Introduction: Due to the high prevalence of viral infections having no specific treatment and the constant emergence of resistant viral strains, searching for effective antiviral compounds is crucial. The present study explores in vitro the antiviral activity of ethanolic extract from aerial parts of Tanacetum vulgare L. against viral strains of three taxonomic groups, including agents that cause socially significant diseases in humans for which antiviral chemotherapy is indicated, namely coxsackievirus B1 (family Picornaviridae), herpes simplex virus type 1 (family Herpesviridae) and influenza A virus (family Orthomyxoviridae). Aim: The aim of the current study was to evaluate antiviral activity of ethanolic extract from herbaceous plant Tanacetum vulgare L. against some important human viruses for which antiviral chemotherapy is needed and to characterize extract for its antioxidant activity in vitro. Materials and methods: The crude aqueous ethanolic extract from aerial parts of Tanacetum vulgare L. contained flavonoids determined as apigenin, coumarins determined as aesculin, tannic compounds determined as tannin, and others. Antiviral activity of ethanolic extract from herbaceous plant Tanacetum vulgare L. against coxsackievirus B1, influenza A and herpes simplex virus type 1 was evaluated by viral yield reduction technique. The total antioxidant activity was determined by measuring the capacity of the sample to inhibit the generation of thiobarbituric acid reactive substances (TBARS). Results: The results show that the extract has the lowest toxicity on the MDBK cell line and similar cytotoxicity in Hep-2, whereas in the MDCK cells it has more than twice the highest toxicity. Testing the antiviral activity of Tanacetum vulgare L. extract revealed a slight inhibition of replication of HSV-1 with a selective index of 7.07 and IAV/H3N2 (SI = 3.69) but no specific antiviral effect against CVB1 replication was found. The evaluation of the antioxidant activity showed great antioxidant activity of the ethanolic extract from T. vulgare – 26 mmol/l for the applied 20 mg/ml extract. Conclusion: The crude extract from aerial parts of the medicinal plant Tanacetum vulgare L. demonstrated low cytotoxicity in Hep-2, MDBK and moderate cytotoxic effects in MDCK cells. It exerted significant antiviral activity against HSV-1 as determined by the recorded inhibition of viral replication, the blockage of virus entry - absorption stage and direct virucidal effects on extracellular virions. The observed effect when testing Tanacetum’s extract on influenza A H3N2 virus infection in vitro was milder, which probably resulted from the interference with the cellular pathways involved in the replication cycle. The presence of virucidal and adsorption-suppressing activity but the absence of viral replication inhibitory effects against CBV-1 suggests a possible interaction of the extract’s components with viral capsid proteins or related cell receptors.

The challenges in combating enteroviruses continue due to their genetic diversity and the rapid development of resistance. Combining antiviral agents offers a promising solution. Our study evaluated the combined effects of pocapavir, a potent capsid-binding inhibitor, with enterovirus-targeting compounds such as pleconaril, 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860), guanidine hydrochloride, oxoglaucine, and 2-α-hydroxybenzyl-benzimidazole (HBB). The combinations tested demonstrated additive to highly synergistic antiviral effects without observed combined cytotoxicity. These results suggest their potential for further research and clinical trials in combating enterovirus infections. [ABSTRACT FROM AUTHOR]

Black Sea freezing in winter is observed regularly in its northern parts and near the Kerch Strait. The reason for this is the relatively shallow northwestern shelf part and the river inflow of the three major European rivers Danube, Dnieper, and Dniester, as well as Don through the Azov Sea, carrying a large amount of fresh water to this part of the Black Sea. The global warming that has been observed in recent decades has made these episodes less intense; nevertheless, they exist and impact people who live n the area. The aim of this study is to analyze the extent of sea-ice variability in the last 15 years, observed by satellite observations, and to describe the weather conditions favorable for freezing to occur. It is found that, in 2006, 2012 and 2017, sea ice extended unusually southward, which is related to the unusually cold winter and weather conditions in these years. The weather patterns associated with the periods of maximal sea ice in the Black Sea are discussed. In addition, we analyze how the winter conditions change in the period 1926–2021 by combining different data sources. The winter is classified as cold, moderate or mild through the Winter Severity Index following a previously published methodology. The findings in our paper could help to monitor and predict these events and to inform the interested end-users.

Post-transcriptional gene silencing is an effective tool for viral replication control at the epigenetic level. In this study, we aimed to produce dsRNAs and siRNA pools targeting the genetic region for the viral protease 3C and the genetic region covering the sequences for VP1 and VP3 capsid proteins of the Coxsackievirus B3 cardiotropic Woodruff strain by the use of the polymerase complex of bacteriophage Phi6 in HEp-2 monolayer cells. The dsRNAs obtained in this study, specific for the 3C and VP1-VP3 genetic regions of the virus, were characterized by very low cytotoxicity (up to 200 nmol/L and 100 nmol/L, respectively) and high efficiency at silencing the target genes and blocking the enteroviral replication in vitro (93% and 60% reduction of the virus infected cells, respectively, at concentrations of 40 nmol/L). The generated pools of overlapping siRNAs targeting the 3C or VP1-VP3 genetic regions showed insignificant cytotoxicity at concentrations up to 200 nmol/L (< 3%) and higher efficacy than the corresponding dsRNAs. We managed to achieve 95% inhibition of the CVB3 Woodruff strain replication in vitro by using siRNAs specific for the 3C coding region of the virus at a concentration of 40 nmol/L, with no cytotoxicity.

Winds, waves and storm surges can inflict severe damage in coastal areas. In order to improve preparedness for such events, a better understanding of storm-induced coastal flooding episodes is necessary. To this end, this paper highlights the use of atmospheric downscaling techniques in order to improve wave and storm surge hindcasts. The downscaling techniques used here are based on existing European Centre for Medium-Range Weather Forecasts reanalyses (ERA-20C, ERA-40 and ERA-Interim). The results show that the 10 km resolution data forcing provided by a downscaled atmospheric model gives a better wave and surge hindcast compared to using data directly from the reanalysis. Furthermore, the analysis of the most extreme mid-latitude cyclones indicates that a four-dimensional blending approach improves the whole process, as it assimilates more small-scale processes in the initial conditions. Our approach has been successfully applied to ERA-20C (the 20th century reanalysis).

Titanium (Ti) is a non-essential metal element. TiO2 is used predominantly in the form of micro and nanoparticles in consumer products, including cosmetics and food. Because of its excellent biocompatibility, the trade-pure titan and its alloys are widely used as an alternative to certain metals in invasive medicine, surgery, dental medicine. Contemporary data concerning the sources of exposure to titanium, immune reactions to Ti alloys, current knowledge and perspectives of diagnosis of sensitization or allergic reactions to titanium are discussed. Conclusion: TiO2 is much more stable than pure Ti and alloys used in the implants, that should be taken into account when conducting research and analysing the results. The evidence of possible toxic effects is insufficient. It is difficult to assess the frequency of Ti allergy due to the uncertainty of diagnostic methods, but it is believed that it is very low. This is supported by the evidence that Ti and TiO2 (often as NP) doesn’t penetrate through the healthy skin. Skin patch testing with currently available formulations of Ti and TiO2 has no significant value in clinical practice, and currently, it is assumed that there is no reliable method for diagnosis Ti allergy. The functional analysis of cytokine release and investigation of genetic characteristics could be useful for individual risk assessment in dental implantology. Such studies may also help to investigate separately early and late implant loss, as well as to develop new diagnostic tools.

Cell lysis is a process in which the outer cell membrane is broken to release intracellular constituents in a way that important information about the DNA or RNA of an organism can be obtained. This article is a thorough review of reported methods for the achievement of effective cellular boundaries disintegration, together with their technological peculiarities and instrumental requirements. The different approaches are summarized in six categories: chemical, mechanical, electrical methods, thermal, laser, and other lysis methods. Based on the results derived from each of the investigated reports, we outline the advantages and disadvantages of those techniques. Although the choice of a suitable method is highly dependent on the particular requirements of the specific scientific problem, we conclude with a concise table where the benefits of every approach are compared, based on criteria such as cost, efficiency, and difficulty.

nfluenza is one of the most contageous viral diseases, caused by influenza virus and affects thousands of people every year. The infection causes changes in the intracellular redox balance, increased production of reactive oxygen species, development of antioxidant deficiency and conditions of oxidative stress. Decreased level of gluthatione during flu is responsible for the severe pathology and complications. The purpose of our studies was to follow the effect of the combination S-adenosyl-L-methionine (SAM) as a precursor of glutathione and the specific neuraminidase inhibitor oseltamivir in influenza infected mice. SAM was given as a single daily dose of 50,100 and 150 mg/kg, starting from 5 days before infection until day 4th after viral inoculation. Oseltamivir was given in a daily dose of 2.5 mg/kg in two intakes for 5 days, starting from 4th hour before infection. End-point evaluation was 14 day survival rate, avarege survival time, index of protection, and virus titer in lungs. The results showed that application of SAM alone did not have any antiviral prevention. In mice supplemented with oseltamivir only survival rate was 70%, but combination of oseltamivir and SAM in lower doses led to rising of 90% of protection. The present findings suggest that combined therapy of SAM as a precursor of glutathione and the specific inhibitor of inflienza virus replication oseltamivir could be effective on modulation of host defense mechanism(s) in low therapeutic doses.

In the present work a detailed numerical study of the parameters influencing the droplet formation in a flow-focusing microfluidic device are made. First, an extensive verification of the simulations with data from the literature is carried out. Influence of parameters like viscosity and inflow velocity are compared with the results from literature showing a good agreement. Some differences are attributed to the different numerical techniques used: in the present work a pure volume-of-fluid method is used, while in the reference study this method is combined with the level-set method. As a second step of the verification of the present model, a comparison with experimental data from the literature was carried out which shows a very good agreement. After the verification was completed, eight new simulations are carried out covering a wide range of velocities of the continuous phase uc. In these simulations the velocity of the discrete phase ud remains unchanged. The variation of the continuous phase velocity reveals that with increasing the value of uc, respectively the value of the capillary number Ca, the droplet length reaches a point of saturation, i.e. a point where the droplet length does not decrease any more. For the present setup this saturation occurs for Ca > 0,03. On the other hand, when the velocity of the continuous phase goes towards very low values (Ca < 0,01 for the present setup), the droplet size increases significantly. Further, it was found that for increasing capillary numbers Ca above a value around 0,015 for water/oil and above 0,025 for water + 40% glycerol / oil systems, a transmission from the dripping towards the jetting regimes of droplet formation occurs. It was shown that when the viscosity of the continuous phase increases, higher total pressure jumps in the droplet occur, also leading to the formation of smaller droplets.

Abstract: The hydrogen bonding between substituted adenines and thymine was investigated by density functional theory computations at the B3LYP/6-311+G(2d,2p) level. The effect of 20 different polar substituents at position 8 in adenine was examined in detail. Three different theoretical parameters, reflecting the electrostatics at the atoms involved in hydrogen bonding, were applied. An excellent correlation between electrostatic potentials at the bonding atoms in the monomer adenines and interaction energies was derived (Eqn. 2). It can be employed in designing bioactive adenine derivatives that are able to bind with a finely adjusted strength to thymine bioreceptor sites. NBO and Hirshfeld atomic charges are found to be less successful as reactivity predictors in these interactions.

Non-Hodgkin lymphoma (NHL) and leukemia are among the most common cancers worldwide. While the treatment of NHL/leukemia of B-cell origin has much progressed with the introduction of targeted therapies, few treatment standards have been established for T-NHL/leukemia. As presentation in both B- and T-NHL/leukemia patients is often aggressive and as prognosis for relapsed disease is especially dismal, this cancer entity poses major challenges and requires innovative therapeutic approaches. In clinical trials, oncolytic viruses (OVs) have been used against refractory multiple myeloma (MM). In preclinical settings, a number of OVs have demonstrated a remarkable ability to suppress various types of hematological cancers. Most studies dealing with this approach have used MM or B- or myeloid-cell-derived malignancies as models. Only a few describe susceptibility of T-cell lymphoma/leukemia to OV infection and killing. The rat H-1 parvovirus (H-1PV) is an OV with considerable promise as a novel therapeutic agent against both solid tumors (pancreatic cancer and glioblastoma) and hematological malignancies. The present perspective article builds on previous reports of H-1PV-driven regression of Burkitt’s lymphoma xenografts and on unpublished observations demonstrating effective killing by H-1PV of cells from CHOP-resistant diffuse large B-cell lymphoma, cutaneous T-cell lymphoma, and T-cell acute lymphoblastic leukemia. On the basis of these studies, H-1PV is proposed for use as an adjuvant to (chemo)therapeutic regimens. Furthermore, in the light of a recently completed first parvovirus clinical trial in glioblastoma patients, the advantages of H-1PV for systemic application are discussed.