Oxygen deficiency is one of the key pathogenetic factors determining development and severity of many diseases, including inflammatory, infectious diseases, and cancer. Lack of oxygen activates the ...signaling pathway of the hypoxia-inducible transcription factor HIF in cells that has three isoforms, HIF-1, HIF-2, HIF-3, regulating expression of several thousand genes. Throughout tumor progression, HIF activation stimulates angiogenesis, promotes changes in cell metabolism, adhesion, invasiveness, and ability to metastasize. HIF isoforms can play opposite roles in the development of inflammatory and neoplastic processes. Humans and laboratory animals differ both in tolerance to hypoxia and in the levels of expression of HIF and HIF-dependent genes, which may lead to predisposition to the development of certain oncological disorders. In particular, the ratio of different histogenetic types of tumors may vary among people living in the mountains and at the sea level. However, despite the key role of hypoxia at almost all stages of tumor development, basal tolerance to oxygen deficiency is not considered as a factor of predisposition to the tumor growth initiation. In literature, there are many works characterizing the level of local hypoxia in various tumors, and suggesting fundamental approaches to its mitigation by HIF inhibition. HIF inhibitors, as a rule, have a systemic effect on the organism, however, basal tolerance of an organism to hypoxia as well as the level of HIF expression are not taken into account in the process of their use. The review summarizes the literature data on different HIF isoforms and their role in tumor progression, with extrapolation to organisms with high and low tolerance to hypoxia, as well as on the prevalence of various types of tumors in the populations living at high altitudes.
Aging is accompanied by a reduction in the oxygen delivery to all organs and tissues and decrease in the oxygen partial pressure in them, resulting in the development of hypoxia. The lack of oxygen ...activates cell signaling pathway mediated by the hypoxia-inducible transcription factor (HIF), which exists in three isoforms – HIF-1, HIF-2, and HIF-3. HIF regulates expression of several thousand genes and is a potential target for the development of new drugs for the treatment of many diseases, including those associated with age. Human organism and organisms of laboratory animals differ in their tolerance to hypoxia and expression of HIF and HIF-dependent genes, which may contribute to the development of inflammatory, tumor, and cardiovascular diseases. Currently, the data on changes in the HIF expression with age are contradictory, which is mostly due to the fact that such studies are conducted in different age groups, cell types, and model organisms, as well as under different hypoxic conditions and mainly
in vitro
. Furthermore, the observed discrepancies can be due to the individual tolerance of the studied organisms to hypoxia, which is typically not taken into account. Therefore, the purpose of this review was to analyze the published data on the connection between the mechanisms of aging, basal tolerance to hypoxia, and changes in the level of HIF expression with age. Here, we summarized the data on the age-related changes in the hypoxia tolerance, HIF expression and the role of HIF in aging, which is associated with its involvement in the molecular pathways mediated by insulin and IGF-1 (IIS), sirtuins (SIRTs), and mTOR. HIF-1 interacts with many components of the IIS pathway, in particular with FOXO, the activation of which reduces production of reactive oxygen species (ROS) and increases hypoxia tolerance. Under hypoxic conditions, FOXO is activated via both HIF-dependent and HIF-independent pathways, which contributes to a decrease in the ROS levels. The activity of HIF-1 is regulated by all members of the sirtuin family, except SIRT5, while the mechanisms of SIRT interaction with HIF-2 and HIF-3 are poorly understood. The connection between HIF and mTOR and its inhibitor, AMPK, has been identified, but its exact mechanism has yet to be studied. Understanding the role of HIF and hypoxia in aging and pathogenesis of age-associated diseases is essential for the development of new approaches to the personalized therapy of these diseases, and requires further research.
Phytoplasmas are insect-transmitted bacterial plant pathogens that cause considerable damage to a diverse range of agricultural crops globally. Symptoms induced in infected plants suggest that these ...phytopathogens may modulate developmental processes within the plant host. We report herein that Aster Yellows phytoplasma strain Witches' Broom (AY-WB) readily infects the model plant Arabidopsis (Arabidopsis thaliana) ecotype Columbia, inducing symptoms that are characteristic of phytoplasma infection, such as the production of green leaf-like flowers (virescence and phyllody) and increased formation of stems and branches (witches' broom). We found that the majority of genes encoding secreted AY-WB proteins (SAPs), which are candidate effector proteins, are expressed in Arabidopsis and the AY-WB insect vector Macrosteles quadrilineatus (Hemiptera; Cicadellidae). To identify which of these effector proteins induce symptoms of phyllody and virescence, we individually expressed the effector genes in Arabidopsis. From this screen, we have identified a novel AY-WB effector protein, SAP54, that alters floral development, resulting in the production of leaf-like flowers that are similar to those produced by plants infected with this phytoplasma. This study offers novel insight into the effector profile of an insect-transmitted plant pathogen and reports to our knowledge the first example of a microbial pathogen effector protein that targets flower development in a host.
We report the synthesis and characterization of amorphous iron oxide nanoparticles from iron salts in aqueous extracts of monocotyledonous (Hordeum vulgare) and dicotyledonous (Rumex acetosa) plants. ...The nanoparticles were characterized by TEM, absorbance spectroscopy, SAED, EELS, XPS, and DLS methods and were shown to contain mainly iron oxide and iron oxohydroxide. H. vulgare extracts produced amorphous iron oxide nanoparticles with diameters of up to 30 nm. These iron nanoparticles are intrinsically unstable and prone to aggregation; however, we rendered them stable in the long term by addition of 40 mM citrate buffer pH 3.0. In contrast, amorphous iron oxide nanoparticles (diameters of 10–40 nm) produced using R. acetosa extracts are highly stable. The total protein content and antioxidant capacity are similar for both extracts, but pH values differ (H. vulgare pH 5.8 vs R. acetosa pH 3.7). We suggest that the presence of organic acids (such oxalic or citric acids) plays an important role in the stabilization of iron nanoparticles, and that plants containing such constituents may be more efficacious for the green synthesis of iron nanoparticles.
Intriguing, yet uncultured 'ARMAN'-like archaea are metabolically dependent on other members of the microbial community. It remains uncertain though which hosts they rely upon, and, because of the ...lack of complete genomes, to what extent. Here, we report the co-culturing of ARMAN-2-related organism, Mia14, with Cuniculiplasma divulgatum PM4 during the isolation of this strain from acidic streamer in Parys Mountain (Isle of Anglesey, UK). Mia14 is highly enriched in the binary culture (ca. 10% genomic reads) and its ungapped 0.95 Mbp genome points at severe voids in central metabolic pathways, indicating dependence on the host, C. divulgatum PM4. Analysis of C. divulgatum isolates from different sites and shotgun sequence data of Parys Mountain samples suggests an extensive genetic exchange between Mia14 and hosts in situ. Within the subset of organisms with high-quality genomic assemblies representing the 'DPANN' superphylum, the Mia14 lineage has had the largest gene flux, with dozens of genes gained that are implicated in the host interaction.In the absence of complete genomes, the metabolic capabilities of uncultured ARMAN-like archaea have been uncertain. Here, Golyshina et al. apply an enrichment culture technique and find that the ungapped genome of the ARMAN-like archaeon Mia14 has lost key metabolic pathways, suggesting dependence on the host archaeon Cuniculiplasma divulgatum.
Hypoxia causes changes in transcription of the genes that contribute to adaptation of the cells to low levels of oxygen. The main mechanism regulating cellular response to hypoxia is activation of ...hypoxia-inducible transcription factors (HIF), which include several isoforms and control expression of more than a thousand genes. HIF activity is regulated at various levels, including by small non-coding RNA molecules called microRNAs (miRNAs). miRNAs regulate cellular response to hypoxia by influencing activation of HIF, its degradation, and translation of HIF-dependent proteins. At the same time, HIFs also affect miRNAs biogenesis. Data on the relationship of a particular HIF isoform with miRNAs are contradictory, since studies have been performed using different cell lines, various types of experimental animals and clinical material, as well as at different oxygen concentrations and durations of hypoxic exposure. In addition, HIF expression may be affected by the initial resistance of organisms to lack of oxygen, which has not been taken into account in the studies. This review analyzes the data on the effect of hypoxia on biogenesis and functioning of miRNAs, as well as on the effect of miRNAs on mRNAs of the genes involved in adaptation to oxygen deficiency. Understanding the mechanisms of relationship between HIF, hypoxia, and miRNA is necessary to develop new approaches to personalized therapy for diseases accompanied by oxygen deficiency.
MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle ...regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
Single-walled carbon nanotubes (SWCNTs) possess the unique ability to tune their functional properties by modifying the outer surface or interior space. Using the same modifier – sulfur, we ...demonstrate a difference in sensing properties of coated and filled single-walled carbon nanotubes to gaseous nitrogen dioxide. A comprehensive investigation of materials by transmission electron microscopy, X-ray photoelectron spectroscopy, density functional theory, and kinetics simulation led to an in-depth understanding of the factors influencing the sensor response of sulfur-modified SWCNTs, such as the role of surface and volumetric processes and interface effects. The sulfur-filled nanotubes with sulfur coating showed an outstanding sensitivity to detect nitrogen dioxide over a range from 1 ppb to 10 ppm due to the involvement of sulfur species in charge transfer between nanotubes and adsorbed molecules. Our data create a platform for the development of sensitive and reversible gas sensors using nanotube-based networks.
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To study the isolates with acquired resistance to bedaquiline and linezolid that were obtained from patients enrolled in a clinical study of a novel therapy regimen for drug-resistant TB in Moscow, ...Russia.
Linezolid resistance was detected using MGIT 960 with a critical concentration of 1 mg/L. The MIC of bedaquiline was determined using the proportion method. To identify genetic determinants of resistance, sequencing of the mmpR ( Rv0678 ), atpE , atpC , pepQ , Rv1979c , rrl , rplC and rplD loci was performed.
A total of 85 isolates from 27 patients with acquired resistance to linezolid and reduced susceptibility to bedaquiline (MIC ≥0.06 mg/L) were tested. Most mutations associated with a high MIC of bedaquiline were found in the mmpR gene. We identified for the first time two patients whose clinical isolates had substitutions D28N and A63V in AtpE, which had previously been found only in in vitro -selected strains. Several patients had isolates with elevated MICs of bedaquiline prior to treatment; four of them also bore mutations in mmpR , indicating the presence of some hidden factors in bedaquiline resistance acquisition. The C154R substitution in ribosomal protein L3 was the most frequent in the linezolid-resistant strains. Mutations in the 23S rRNA gene (g2294a and g2814t) associated with linezolid resistance were also found in two isolates. Heteroresistance was identified in ∼40% of samples, which reflects the complex nature of resistance acquisition.
The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance.
Circulating tumor cells (CTCs) disseminated into peripheral blood from a primary, or metastatic, tumor can be used for early detection, diagnosis and monitoring of solid malignancies. CTC isolation ...by size exclusion techniques have long interested researchers as a simple broad based approach, which is methodologically diverse for use in both genomic and protein detection platforms. Though a variety of these microfiltration systems are employed academically and commercially, the limited ability to easily alter microfilter designs has hindered the optimization for CTC capture. To overcome this problem, we studied a unique photo-definable material with a scalable and mass producible photolithographic fabrication method. We use this fabrication method to systematically study and optimize the parameters necessary for CTC isolation using a microfiltration approach, followed by a comparison to a "standard" filtration membrane. We demonstrate that properly designed microfilters can capture MCF-7 cancer cells at rate of 98 ± 2% if they consist of uniform patterned distributions, ≥160 000 pores, and 7 μm pore diameters.
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