Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles ...to improve current treatments is represented by the impermeability of the blood vessels residing within nervous tissue as well as of the new vascular net generating from the tumor, commonly referred to as blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively. In this review, we focused on established and emerging strategies to overcome the blood-brain barrier to increase drug delivery for brain cancer. To date, there are three broad strategies being investigated to cross the brain vascular wall and they are conceived to breach, bypass, and negotiate the access to the nervous tissue. In this paper, we summarized these approaches highlighting their working mechanism and their potential impact on the quality of life of the patients as well as their current status of development.
Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects about 1% of the world's population. The etiology of RA remains unknown. It is considered to occur in the presence of genetic ...and environmental factors. An increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of RA pathogenesis. Epigenetics causes heritable phenotype changes that are not determined by changes in the DNA sequence. The major epigenetic mechanisms include DNA methylation, histone proteins modifications and changes in gene expression caused by microRNAs and other non-coding RNAs. These modifications are reversible and could be modulated by diet, drugs, and other environmental factors. Specific changes in DNA methylation, histone modifications and abnormal expression of non-coding RNAs associated with RA have already been identified. This review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.
Recently, high-throughput sequencing of influenza A viruses has become a routine test. It should be noted that the extremely high diversity of the influenza A virus complicates the task of ...determining the sequences of all eight genome segments. For a fast and accurate analysis, it is necessary to select the most suitable reference for each segment. At the same time, there is no standardized method in the field of decoding sequencing results that allows the user to update the sequence databases to which the reads obtained by virus sequencing are compared. The IAVCP (influenza A virus consensus and phylogeny) was developed with the goal of automatically analyzing high-throughput sequencing data of influenza A viruses. Its goals include the extraction of a consensus genome directly from paired raw reads. In addition, the pipeline enables the identification of potential reassortment events in the evolutionary history of the virus of interest by analyzing the topological structure of phylogenetic trees that are automatically reconstructed.
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course ...options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.
Phylodynamics of Crimean Congo Hemorrhagic fever virus (CCHFV) genotype V in South Russia was analyzed using 244 partial (452–571 nt) sequences in all three genomic segments and 38 complete genomic ...sequences. Despite increased number of sequences, the Russian lineage of the European genotype V (commonly termed GtVa) was distinct from GtV isolates from Turkey and the Balkan countries. No geographic pattern was observed in phylogenetic subgrouping of CCHFV within South Russia. Identical isolates could be found at distant locations spaced by hundreds of kilometers, while relatively divergent viruses circulated in the same region. Full genome analysis indicated that reassortment events within GtVa occurred every few decades (median half-life of a non-reassortant node 30–40 years) and involved M and S segments. Therefore, in South Russia CCHFV represents a highly dynamic population of frequently reassorting viruses.
•A comprehensive analysis of Crimean Congo Hemorrhagic fever virus (CCHFV) phylodynamics in South Russia was conducted;•CCHFV represents a highly dynamic population of frequently reassorting viruses;•Reassortment events within the Russian lineage of the European genotype V (GtVa) occurred every 30-40 years;
Currently, the lowest formal taxon in virus classification is species; however, unofficial lower-level units are commonly used in everyday work.
(
) is a species of mammalian tick-borne flaviviruses ...that may cause encephalitis. Many known representatives of
are grouped into subtypes, mostly according to their phylogenetic relationship. However, the emergence of novel sequences could dissolve this phylogenetic grouping; in the absence of strict quantitative criterion, it may be hard to define the borders of the first TBEV taxonomic unit below the species level. In this study, the nucleotide/amino-acid space of all known TBEV sequences was analyzed. Amino-acid sequence
-distances could not reliably distinguish TBEV subtypes. Viruses that differed by less than 10% of nucleotides in the polyprotein-coding gene belonged to the same subtype. At the same time, more divergent viruses were representatives of different subtypes. According to this distance criterion,
species may be divided into seven subtypes: TBEV-Eur, TBEV-Sib, TBEV-FE, TBEV-2871 (TBEV-Ob), TBEV-Him, TBEV-178-79 (TBEV-Bkl-1), and TBEV-886-84 (TBEV-Bkl-2).
Near complete rabies virus N gene sequences (1,110 nt) were determined for 82 isolates obtained from different regions of Russia between 2008 and 2016. These sequences were analyzed together with 108 ...representative GenBank sequences from 1977-2016 using the Bayesian coalescent approach. The timing of the major evolutionary events was estimated. Most of the isolates represented the steppe rabies virus group C, which was found over a vast geographic region from Central Russia to Mongolia and split into three groups (C0-C2) with discrete geographic prevalence. A single strain of the steppe rabies virus lineage was isolated in the far eastern part of Russia (Primorsky Krai), likely as a result of a recent anthropogenic introduction. For the first time the polar rabies virus group A2, previously reported in Alaska, was described in the northern part of European Russia and at the Franz Josef Land. Phylogenetic analysis suggested that all currently circulating rabies virus groups in the Russian Federation were introduced within the few last centuries, with most of the groups spreading in the 20th century. The dating of evolutionary events was highly concordant with the historical epidemiological data.
The aim
To study the association of demographic, clinical, and laboratory factors and the use of glucose-lowering drugs and anti-coronavirus disease (COVID-19) vaccination with the COVID-19-related ...case fatality rate (CFR) in diabetes mellitus (DM) patients.
Methods
This study is a nationwide observational cohort study based on the data from the National Diabetes Register (NDR) that is the database containing online clinical information about the population with DM. The outcomes (death or recovery) for COVID-19 were registered in 235,248 patients with DM type 1 diabetes mellitus (T1DM), n = 11,058; type 2 diabetes mellitus (T2DM), n = 224,190 from March 20, 2020, until November 25, 2021. The unadjusted odds ratio (OR) and 95% confidence interval (CI) were used to estimate the risk factors for CFR. Then the ranging of significant factors was performed and the most vulnerable groups of factors for the lethal outcome were chosen.
Results
The CFR due to COVID-19 was 8.1% in T1DM and 15.3% in T2DM. Increased CFR was associated with the male population OR = 1.25 (95% CI: 1.09–1.44) in T1DM and 1.18 (95% CI: 1.15–1.21) in T2DM, age ≥65 years OR = 4.44 (95% CI: 3.75–5.24) in T1DM and 3.18 (95% CI: 3.09–3.26) in T2DM, DM duration ≥10 years OR = 2.46 (95% CI: 2.06–2.95) in T1DM and 2.11 (95% CI: 2.06–2.16) in T2DM, body mass index (BMI) ≥30 kg/m
2
OR = 1.95 (95% CI: 1.52–2.50) in T1DM, HbA1c ≥7% OR = 1.35 (95% CI: 1.29–1.43) in T2DM. The atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD) were associated with higher CFR in T1DM but not in T2DM. The pre-COVID-19 glucose-lowering therapy in T2DM was differently associated with CFR (OR): 0.61 (95% CI: 0.59–0.62) for metformin, 0.59 (95% CI: 0.57–0.61) for dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), 0.46 (95% CI: 0.44–0.49) for sodium-glucose co-transporter-2 (SGLT2) inhibitors, 0.38 (95% CI: 0.29–0.51) for glucagon-like peptide-1 receptor agonists (arGLP-1), 1.34 (95% CI: 1.31–1.37) for sulfonylurea (SU), and 1.47 (95% CI: 1.43–1.51) for insulin. Anti-COVID-19 vaccination was associated with a lower fatality risk in both DM types: OR = 0.07 (95% CI: 0.03–0.20) in T1DM and OR = 0.19 (95% CI: 0.17–0.22) in T2DM.
Conclusions
The results of our study suggest that increased COVID-19-related fatality risk in both T1DM and T2DM patients associated with the male population, older age, longer DM duration, and absence of anti-COVID-19 vaccination. In T2DM, pre-COVID-19 glucose-lowering therapy with metformin, DPP-4 inhibitors, SGLT2 inhibitors, and arGLP-1 had a positive effect on the risk of death. The most vulnerable combination of risk factors for lethal outcome in both DM types was vaccine absence + age ≥65 years + DM duration ≥10 years.
Tick-borne encephalitis (TBE) is one of the most important viral zoonosis transmitted by the bite of infected ticks. In this study, all tick-borne encephalitis virus (TBEV) E gene sequences available ...in GenBank as of June 2019 with known date of isolation (
= 551) were analyzed. Simulation studies showed that a sample bias could significantly affect earlier studies, because small TBEV datasets (
= 50) produced non-overlapping intervals for evolutionary rate estimates. An apparent lack of a temporal signal in TBEV, in general, was found, precluding molecular clock analysis of all TBEV subtypes in one dataset. Within all subtypes and most of the smaller groups in these subtypes, there was evidence of many medium- and long-distance virus transfers. These multiple random events may play a key role in the virus spreading. For some groups, virus diversity within one territory was similar to diversity over the whole geographic range. This is best exemplified by the virus diversity observed in Switzerland or Czech Republic. These two countries yielded most of the known European subtype Eu3 subgroup sequences, and the diversity of viruses found within each of these small countries is comparable to that of the whole Eu3 subgroup, which is prevalent all over Central and Eastern Europe. Most of the deep tree nodes within all three established TBEV subtypes dated less than 300 years back. This could be explained by the recent emergence of most of the known TBEV diversity. Results of bioinformatics analysis presented here, together with multiple field findings, suggest that TBEV may be regarded as an emerging disease.
Plants, including
L., are constantly attacked by various pathogens which induce immune responses. Immune processes in plants are tightly regulated by proteases from different families within their ...degradome. In this study, a wheat degradome was characterized. Using profile hidden Markov model (HMMer) algorithm and Pfam database, comprehensive analysis of the
genome revealed a large number of proteases (1544 in total) belonging to the five major protease families: serine, cysteine, threonine, aspartic, and metallo-proteases. Mass-spectrometry analysis revealed a 30% difference between degradomes of distinct wheat cultivars (Khakasskaya and Darya), and infection by biotrophic (
Rob. ex Desm f. sp. tritici) or necrotrophic (
) pathogens induced drastic changes in the presence of proteolytic enzymes. This study shows that an early immune response to biotic stress is associated with the same core of proteases from the C1, C48, C65, M24, M41, S10, S9, S8, and A1 families. Further liquid chromatography-mass spectrometry (LC-MS) analysis of the detected protease-derived peptides revealed that infection by both pathogens enhances overall proteolytic activity in wheat cells and leads to activation of proteolytic cascades. Moreover, sites of proteolysis were identified within the proteases, which probably represent targets of autocatalytic activation, or hydrolysis by another protease within the proteolytic cascades. Although predicted substrates of metacaspase-like and caspase-like proteases were similar in biotrophic and necrotrophic infections, proteolytic activation of proteases was not found to be associated with metacaspase-like and caspase-like activities. These findings indicate that the response of
to biotic stress is regulated by unique mechanisms.
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