Search

Introduction. The key step in agent-based modeling of epidemics, which allows researchers to take into account individual characteristics of people, is the creation of an artificial population. The main difficulty of this procedure is finding a balance between the detail of the population description and the computational efficiency of the calculations. The aim and objectives of the review: Critically analyze and summarize the current evidence on how to create artificial populations; evaluate the limitations and advantages of available approaches in solving various problems in epidemiology. Materials and methods. An analysis of literature sources devoted to agent-based modeling has been performed. The analysis is focused on algorithms for creating an artificial population with a given level of detail for modeling human respiratory infections. Results. The approaches to the creation of artificial populations are generalized. The main principles of realization of interaction between agents are revealed: by means of networks of contacts between agents and on the basis of taking into account the movement of agents between locations. The first approach is the most computationally efficient and simple; the second approach allows to better take into account the change in the behavior of agents during the development of the epidemic process. Conclusion. Agent-based modeling is an optimal tool for selecting the best scenario for epidemic control and investigating the role of individual characteristics of people in the development of epidemics. When creating an artificial population, it is important to include in the model factors that can be targeted for control. A significant limitation is the lack of factual data on population structure, but this can be overcome by using indirect data.

Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations.

Aim. Compare the lytic efficiency and the kinetics of accumulation of vesicular stomatitis virus serotypes Indiana (VSV-IND) and New Jersey (VSV-NJ) on cell lines of mouse melanoma B16F10, human hepatocellular carcinoma HepG2 and human mammary adenocarcinoma MCF7.Materials and methods. The viability of mouse melanoma B16F10, human hepatocellular carcinoma HepG2 and human mammary adenocarcinoma MCF7 cell lines infected with VSV-IND and VSV-NJ viruses at different multiplicity of infection (10 MOI; 1 MOI; 0.1 MOI) was assessed after 24, 48 and 72 hours, and the half maximal inhibitory concentration (IC50) values were measured using the methyl tetrazolium test. The relationship with virus accumulation in cell culture was determined using reverse transcription – quantitative polymerase chain reaction; 50% tissue culture infectious dose (TCID50) of VSV-IND and VSV-NJ for B16F10, HepG2, MCF7 were calculated using the Reed-Muench method.Results. The most susceptible cell line for both viruses was B16F10: cell viability 72 hours after infection at 10 MOI was only 10.4% and 5.7% for VSV-IND and VSV-NJ, respectively. HepG2 cell viability at 72 hours post-infection at 10 MOI was 10.8% and 9.8% for VSV-IND and VSV-NJ, and for MCF7 adenocarcinoma it was 46.6% and 36.2%, respectively. Moreover, only in the B16F10 culture was a positive statistically significant correlation of medium strength established between the inhibition of cell viability and the accumulation of viral RNA: for VSV-IND r = 0.601 (p < 0.05); for VSV-NJ r = 0.668 (p < 0.05). HepG2 and MCF7 showed no significant correlation.Conclusion. The research results indicate the potential of using oncolytic viruses of the VSV-IND and VSV-NJ as a platform for the development of new recombinant viruses for virotherapy of solid tumors in combination with other types of treatment.

Orthoflaviviruses are arthropod-borne viruses that are transmitted by mosquitoes or ticks and cause a range of significant human diseases. Among the most important tick-borne orthoflaviviruses (TBFVs) is tick-borne encephalitis virus (TBEV), which is endemic in Eurasia, and Powassan virus, which is endemic in Asia and North America. There is a significant controversy regarding species assignment in the tick-borne encephalitis virus complex due to the complex phylogenetic, serological, ecological, and pathogenetic properties of viruses. Comparing the rate of non-synonymous to synonymous substitutions (dN/dS) over the course of tick-borne orthoflavivirus diversification suggests that there is a very strong stabilizing selection (Nei-Gojobori dN/dS < 0.1) among tick-borne orthoflaviviruses that differ by less than 13.5% amino acid/21.4% nucleotide sequences, and discretely more rapid accumulation of non-synonymous substitutions (dN/dS > 0.13) among more divergent viruses that belong to distinct species. This pattern was similarly observed in genome regions encoding structural (E) and non-structural (NS3) proteins. Below this distance threshold, viruses appear fit and strongly tied to their ecological niche, whereas above the threshold, a greater degree of adaptation appears necessary. This species criterion suggests that all subtypes of TBEV, all related ovine/caprine encephalomyelitis viruses, and Omsk hemorrhagic fever virus (OHFV) together correspond to a single species. Within this species, viruses make up 11 subtypes that are reliably segregated by a 10% nucleotide distance cut-off suggested earlier for TBEV. The same 10% subtype cut-off suggests that Powassan virus includes two subtypes, Powassan and Deer Tick virus.

Spin-gapless semiconductor (SGS) is a new class of material that has been studied recently for potential applications in spintronics. This material behaves as an insulator for one spin channel, and as a gapless semiconductor for the opposite spin. In this work, we present results of a computational study of two quaternary Heusler alloys, MnCrNbAl and MnCrTaAl that have been recently reported to exhibit spin-gapless semiconducting electronic structure. In particular, using density functional calculations we analyze the effect of external pressure on electronic and magnetic properties of these compounds. It is shown that while these two alloys exhibit nearly SGS behavior at optimal lattice constants and at negative pressure (expansion), they are half-metals at equilibrium, and magnetic semiconductors at larger lattice constant. At the same time, reduction of the unit cell volume has a detrimental effect on electronic properties of these materials, by modifying the exchange splitting of their electronic structure and ultimately destroying their half-metallic/semiconducting behavior. Thus, our results indicate that both MnCrNbAl and MnCrTaAl may be attractive for practical device applications in spin-based electronics, but a potential compression of the unit cell volume (e.g. in thin-film applications) should be avoided.

APOBEC/AID cytidine deaminases play an important role in innate immunity and antiviral defenses and were shown to suppress hepatitis B virus (HBV) replication by deaminating and destroying the major form of HBV genome, covalently closed circular DNA (cccDNA), without toxicity to the infected cells. However, developing anti-HBV therapeutics based on APOBEC/AID is complicated by the lack of tools for activating and controlling their expression. Here, we developed a CRISPR-activation-based approach (CRISPRa) to induce APOBEC/AID transient overexpression (>4–800,000-fold increase in mRNA levels). Using this new strategy, we were able to control APOBEC/AID expression and monitor their effects on HBV replication, mutation, and cellular toxicity. CRISPRa prominently reduced HBV replication (∼90%–99% decline of viral intermediates), deaminated and destroyed cccDNA, but induced mutagenesis in cancer-related genes. By coupling CRISPRa with attenuated sgRNA technology, we demonstrate that APOBEC/AID activation can be precisely controlled, eliminating off-site mutagenesis in virus-containing cells while preserving prominent antiviral activity. This study untangles the differences in the effects of physiologically expressed APOBEC/AID on HBV replication and cellular genome, provides insights into the molecular mechanisms of HBV cccDNA mutagenesis, repair, and degradation, and, finally, presents a strategy for a tunable control of APOBEC/AID expression and for suppressing HBV replication without toxicity.

Introduction. The black-faced are mentioned in different Muslim texts — from the Quran to Sufi poems. One can trace not just diverse but rather opposite interpretations, and researchers have to face certain problems when it comes to analyze some related images. Goals. The study attempts an insight into functioning and semantic features inherent to images of the black-faced in Sufi poetry. Materials and methods. The work analyzes a number of classical Persian and Arabic writings, such as The Walled Garden of Truth by Sanai, and others. The employed research methods include those of textual reconstruction, contextual analysis, and descriptive poetics. Results. The paper shows in medieval Islamic culture the black-skinned were often treated not just as second-class individuals, they were sometimes not even viewed as humans. In the Quran, a black face symbolizes disgrace and infidelity. The blacks in Islamic culture were discriminated twice: by skin color and on religious grounds, since most of them were pagans that actively resisted Islamization. This circumstance served a legal rationale for their enslavement. Thus, for many Arab writers a black was a slave, an uncivilized ungodly pagan. These characteristics one can find both in Arabic and Persian literatures. But in Persian Sufism the image of the black-skinned gets revisited. Their outward blackness is the trace of the black light of the divine selfness rather than just an ugly imperfection. The Divine selfness is dark for it cannot be conceived, and is above all human ideas about it. However, the Divine selfness is the being itself, so every existent thing had received being from this Divine source. In this context, Sanai writes that a black-faced is singed by the black light (or fire) of the Divine selfness, and is thus involved with this being. Besides, Sufis tended to view the low social status of the black as a means of liberation from worldly attachments and social connections, each black-skinned individual be thus believed to have united with the One Divine selfness to annihilate his own self (fana). Conclusions. So, the image of the black-faced performs functions similar to those characteristic of a wide layer of characters from other religions in Sufi literature: just like images of infidels, pagans, Zoroastrians, and Christians — this was reinterpreted by Sufi authors in a positive manner.

The epitranscriptomic modification m6A is a prevalent RNA modification that plays a crucial role in the regulation of various aspects of RNA metabolism. It has been found to be involved in a wide range of physiological processes and disease states. Of particular interest is the role of m6A machinery and modifications in viral infections, serving as an evolutionary marker for distinguishing between self and non-self entities. In this review article, we present a comprehensive overview of the epitranscriptomic modification m6A and its implications for the interplay between viruses and their host, focusing on immune responses and viral replication. We outline future research directions that highlight the role of m6A in viral nucleic acid recognition, initiation of antiviral immune responses, and modulation of antiviral signaling pathways. Additionally, we discuss the potential of m6A as a prognostic biomarker and a target for therapeutic interventions in viral infections.

CRISPR-Cas9 systems can directly target the hepatitis B virus (HBV) major genomic form, covalently closed circular DNA (cccDNA), for decay and demonstrate remarkable anti-HBV activity. Here, we demonstrate that CRISPR-Cas9-mediated inactivation of HBV cccDNA, frequently regarded as the “holy grail” of viral persistence, is not sufficient for curing infection. Instead, HBV replication rapidly rebounds because of de novo formation of HBV cccDNA from its precursor, HBV relaxed circular DNA (rcDNA). However, depleting HBV rcDNA before CRISPR-Cas9 ribonucleoprotein (RNP) delivery prevents viral rebound and promotes resolution of HBV infection. These findings provide the groundwork for developing approaches for a virological cure of HBV infection by a single dose of short-lived CRISPR-Cas9 RNPs. Blocking cccDNA replenishment and re-establishment from rcDNA conversion is critical for completely clearing the virus from infected cells by site-specific nucleases. The latter can be achieved by widely used reverse transcriptase inhibitors.

More than 100 types of non-polio enteroviruses (NPEVs) are ubiquitous in the human population and cause a variety of symptoms ranging from very mild to meningitis and acute flaccid paralysis (AFP). Much of the information regarding diverse pathogenic properties of NPEVs comes from the surveillance of poliovirus, which also yields NPEV. The analysis of 265 NPEV isolations from 10,433 AFP cases over 24 years of surveillance and more than 2500 NPEV findings in patients without severe neurological lesions suggests that types EV-A71, E13, and E25 were significantly associated with AFP. EV-A71 was also significantly more common among AFP patients who had fever at the onset and residual paralysis compared to all AFP cases. In addition, a significant disparity was noticed between types that were common in humans (CV-A2, CVA9, EV-A71, E9, and E30) or in sewage (CVA7, E3, E7, E11, E12, and E19). Therefore, there is significant evidence of non-polio viruses being implicated in severe neurological lesions, but further multicenter studies using uniform methodology are needed for a definitive conclusion.

We present computational results on electronic, magnetic, and structural properties of CoVMnSb, a quaternary Heusler alloy. Our calculations indicate that this material may crystallize in two energetically close structural phases: inverted and regular cubic. The inverted cubic phase is the ground state, with ferrimagnetic alignment, and around 80% spin polarization. Despite having a relatively large bandgap in the minority-spin channel close to the Fermi level, this phase does not undergo a half-metallic transition under pressure. This is explained by the "pinning" of the Fermi level at the minority-spin states at the Γ point. At the same time, the regular cubic phase is half-metallic and retains its perfect spin polarization under a wide range of mechanical strain. Transition to a regular cubic phase may be attained by applying uniform pressure (but not biaxial strain). In practice, this pressure may be realized by an atomic substitution of non-magnetic atoms (Sb) with another non-magnetic atom (Si) of a smaller radius. Our calculations indicate that 25% substitution of Sb with Si results in a half-metallic regular cubic phase being the ground state. In addition, CoVMnSb0.5Si0.5 retains its half-metallic properties under a considerable range of mechanical pressure, as well as exhibits thermodynamic stability, thus making this alloy attractive for potential spintronic applications. We hope that the presented results will stimulate experimental efforts to synthesize this compound. [ABSTRACT FROM AUTHOR]

Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations. [ABSTRACT FROM AUTHOR]

Orthoflaviviruses are arthropod-borne viruses that are transmitted by mosquitoes or ticks and cause a range of significant human diseases. Among the most important tick-borne orthoflaviviruses (TBFVs) is tick-borne encephalitis virus (TBEV), which is endemic in Eurasia, and Powassan virus, which is endemic in Asia and North America. There is a significant controversy regarding species assignment in the tick-borne encephalitis virus complex due to the complex phylogenetic, serological, ecological, and pathogenetic properties of viruses. Comparing the rate of non-synonymous to synonymous substitutions (dN/dS) over the course of tick-borne orthoflavivirus diversification suggests that there is a very strong stabilizing selection (Nei-Gojobori dN/dS < 0.1) among tick-borne orthoflaviviruses that differ by less than 13.5% amino acid/21.4% nucleotide sequences, and discretely more rapid accumulation of non-synonymous substitutions (dN/dS > 0.13) among more divergent viruses that belong to distinct species. This pattern was similarly observed in genome regions encoding structural (E) and non-structural (NS3) proteins. Below this distance threshold, viruses appear fit and strongly tied to their ecological niche, whereas above the threshold, a greater degree of adaptation appears necessary. This species criterion suggests that all subtypes of TBEV, all related ovine/caprine encephalomyelitis viruses, and Omsk hemorrhagic fever virus (OHFV) together correspond to a single species. Within this species, viruses make up 11 subtypes that are reliably segregated by a 10% nucleotide distance cut-off suggested earlier for TBEV. The same 10% subtype cut-off suggests that Powassan virus includes two subtypes, Powassan and Deer Tick virus. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon.

The evolution in Leishmania is governed by the opposite forces of clonality and sexual reproduction, with vicariance being an important factor. As such, Leishmania spp. populations may be monospecific or mixed. Leishmania turanica in Central Asia is a good model to compare these two types. In most areas, populations of L. turanica are mixed with L. gerbilli and L. major. Notably, co-infection with L. turanica in great gerbils helps L. major to withstand a break in the transmission cycle. Conversely, the populations of L. turanica in Mongolia are monospecific and geographically isolated. In this work, we compare genomes of several well-characterized strains of L. turanica originated from monospecific and mixed populations in Central Asia in order to shed light on genetic factors, which may drive evolution of these parasites in different settings. Our results illustrate that evolutionary differences between mixed and monospecific populations of L. turanica are not dramatic. On the level of large-scale genomic rearrangements, we confirmed that different genomic loci and different types of rearrangements may differentiate strains originated from mixed and monospecific populations, with genome translocations being the most prominent example. Our data suggests that L. turanica has a significantly higher level of chromosomal copy number variation between the strains compared to its sister species L. major with only one supernumerary chromosome. This suggests that L. turanica (in contrast to L. major) is in the active phase of evolutionary adaptation.

We have carried out joint theoretical and experimental investigations of three Heusler compounds CoMoFeAl, CoMo0.5Fe1.5Al, and Co1.5Mo0.5FeAl. Our first-principle calculations show that all three compounds show either ferro- or ferrimagnetic order with CoMoFeAl and CoMo0.5Fe1.5Al exhibiting high spin polarization of almost 80%. The investigated samples were prepared using arc melting and high vacuum annealing. All the samples show cubic crystal structure with disorder. The parent compound CoMoFeAl shows a small saturation magnetization of 12 emu/g, and a Curie temperature of 440 K. The other two compounds, namely, Co1.5Mo0.5FeAl and CoMo0.5Fe1.5Al, show much higher saturation magnetizations of 62 emu/g and 59 emu/g, and substantially higher Curie temperatures of 950 K and 780 K, respectively.

We have carried out a combined theoretical and experimental investigation of both stoichiometric and nonstoichiometric CoFeVGe alloys. In particular, we have investigated CoFeVGe, Co1.25Fe0.75VGe, Co0.75Fe1.25VGe, and CoFe0.75VGe bulk alloys. Our first principles calculations suggest that all four alloys show ferromagnetic order, where CoFeVGe, Co1.25Fe0.75VGe, and Co0.75Fe1.25VGe are highly spin polarized with spin polarization values of over 80%. However, the spin polarization value of CoFe0.75VGe is only about 60%. We have synthesized all four samples using arc melting and high-vacuum annealing at 600 °C for 48 hours. The room temperature x-ray diffraction of these samples exhibits a cubic crystal structure with disorder. All the samples show single magnetic transitions at their Curie temperatures, where the Curie temperature and high field (3T) magnetization are 288 K and 42 emu/g; 305 K and 1.5 emu/g; 238 K and 39 emu/g; and 306 K and 35 emu/g for CoFeVGe, Co1.25Fe0.75VGe, Co0.75Fe1.25VGe, and CoFe0.75VGe, respectively.