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Changes in the N-glycosylation of immunoglobulin G (IgG) are often observed in pathological states, such as autoimmune, inflammatory, neurodegenerative, cardiovascular diseases and some types of cancer. However, in most cases, it is not clear if the disease onset causes these changes, or if the changes in IgG N-glycosylation are among the risk factors for the diseases. The aim of this study was to investigate the casual relationships between IgG N-glycosylation traits and 12 diseases, in which the alterations of IgG N-glycome were previously reported, using two sample Mendelian randomization (MR) approach. We have performed two sample MR using publicly available summary statistics of genome-wide association studies of IgG N-glycosylation and disease risks. Our results indicate positive causal effect of systemic lupus erythematosus (SLE) on the abundance of N-glycans with bisecting N-acetylglucosamine in the total IgG N-glycome. Therefore, we suggest regarding this IgG glycosylation trait as a biomarker of SLE. We also emphasize the need for more powerful GWAS studies of IgG N-glycosylation to further elucidate the causal effect of IgG N-glycome on the diseases.

Purpose.Analysis of the immediate results of emergency glomus-sparing auto-transplantation of the internal carotid artery (ICA) in the acute period of ischemic stroke, developed on the basis of the City Alexandrovskaya Hospital, St. Petersburg.Material and methods.In this prospective, single-center study from January 2017 to August 2020. 49 patients were included in the acute period of ischemic stroke with hemodynamically significant extended atherosclerotic lesions of the ICA. All patients underwent glomus-sparing ICA autotransplantation, developed on the basis of the City Alexandrovskaya Hospital, St. Petersburg (Kazantsev A. N., Zarkua N. E., Chernykh K. P. et al. Аrteries with extended atherosclerotic lesions of the internal carotid artery. Patent application No. 202.013.4151/14 (062595), filing date 10/16/2020). Glomus-sparing ICA autotransplantation, developed on the basis of the City Alexandrovskaya Hospital, St. Petersburg, was performed as follows. On the inner edge of the external carotid artery (ECA), adjacent to the carotid sinus, 2–3 cm above the orifice, depending on the spread of atherosclerotic plaque (ASB), arteriotomy was performed with the transition to the common carotid artery (CCA) (also 2–3 see below the mouth of the NSA). The ICA was cut off at the site formed by the sections of the wall of the NSA and the CCA. Then the ICA was cut off as distally as possible in front of the hypoglossal nerve, so that the artery was completely resected. In view of the presence of an intact carotid glomus on the resected area of the ICA, which connects it to the wound, endarterectomy from the ICA was performed inside the operating field by its complete eversion. Then, open endarterectomy from ECA and CCA was performed. At the next stage, the ICA was implanted in its previous place with the creation of proximal and distal end-to-end anastomoses, so that the continuing ASB above the endarterectomy zone was fixed with a circular vascular suture.Results.There were no complications in the postoperative period. No cases of restenosis / thrombosis of the reconstruction zone were identified in all the sample according to the color duplex scanning data. On the 7th day after the operation, all patients were diagnosed with regression of neurological symptoms according to the National Institute of Health Stroke Scale: on admission, the mean score was 10.5±3.5; at the moment of the control point — 6.5±1.5; p=0.001. This reflects the effectiveness of the chosen treatment strategy. According to the data on the dynamics of systolic blood pressure, stable systolic parameters were observed in the postoperative period against the background of antihypertensive therapy taken before the operation.Conclusion.Carotid endarterectomy in the acute period of ischemic stroke is safe in the presence of mild neurological deficits (up to 25 points on the National Institute of Health Stroke Scale) and the diameter of the ischemic focus in the brain not exceeding 2.5 cm according to the computer data. tomography. Glomussparing ICA autotransplantation, developed on the basis of the Aleksandrovskaya Hospital, St. Petersburg, does not require the use of a patch and is not characterized by the risk of developing ICA thrombosis as a result of intimal detachment behind the endarterectomy zone. Preservation of the carotid glomus during reconstructive intervention on the ICA prevents the development of labile arterial hypertension and hemorrhagic transformation in the postoperative period.

The Olistostrome member of the Sana-Una Paleozoic complex of the Ljubija ore mine in Bosnia and Herzegovina contains limestone fragments of pebble to block size that have been examined paleontologically. The recovered conodont fauna of the first sample is characterized by the species Declinognathodus lateralis, Idiognathoides sulcatus sulcatus and Idiognathodus sp. confirming its mid-Bashkirian age. This report is the first on the occurrence of these taxa in the area. The second sample with chaetetid demosponges yields an abundant diversified microbiota consisting of cyanobacteria, algae and foraminifera. Chlorophyts are marked by the common siphonoclad occurrence of Donezella lutugini and D. lunaensis, whereas rhodophyts include rare representatives of Stacheia, Stacheoides, Pseudoungdarella and Masloviporidium. The presence of Asphaltinella horowitzi and Aphralysia carbonaria of unclear taxonomic position is also documented. Pseudostaffellids, eostaffellids and other foraminifera, mostly endothyrids are present. The examined associations of fossils point to the Bashkirian age of the primary rock that originated in a very shallow habitat most probably linked to a high-energy reef environment.

The current state of studies on application and safety of food additives in various technologies for food production is examined. Considerable attention should be given to studies dedicated to analysis of food safety criteria due to a possibility of appearance of adverse consequences for human health and the trend towards increasing life quality. Special emphasis is placed on such parameters as genotoxicity and mutagenicity. It is shown that the most rapid and convenient tool for complex monitoring of product toxicity can be the bioassay procedure. Based on the review of the literature on bioassays for edible meat and meat products, canned foods, carbonated soft drinks, beer, milk and milk containing products as well as seasonings, the authors show that above mentioned products had the cyto- and genotoxic potential when tested on animal and human cell cultures, microorganisms and plants. With that, it was found that a list of relevant publications is quite small despite a significant growth in scientific research dedicated to food toxicity assessment using bioassays. A review on the conducted research on assessment of genotoxic and mutagenic effects of foods by bioassay methods will make it possible to extend the understanding of the processes and mechanisms of this toxicity and form more rational concept of consumption.

In recent years, the idea about the physiological significance of neutrophils, including during pregnancy and childbirth, has evolved significantly. There is an opinion that in the course of pregnancy, the activity of non-specific cellular immunity increases, which, in addition to performing a protective function, forms a mode of contractile activity of the uterus that is optimal for child-bearing. In obstetric practice, in order to reduce uterine hypertonicity in the treatment of miscarriage, β-adrenergic agonists are widely used. However, many aspects of their influence on the mother and the foetus remain insufficiently studied. The aim of this paper was to study the effect of Gynipral (selective β2-adrenergic agonist) on the intensity of latex-induced respiratory burst of venous blood neutrophils in women at different stages of reproduction. Using the chemiluminescence method, we showed for the first time that Gynipral, depending on the stage of reproduction, has multidirectional effect on the latex-induced radical activity of neutrophils in the venous blood of women in vitro. At a low level of radical reaction of neutrophils to latex (in the follicular phase of the cycle, during pregnancy and, which is especially important, during childbirth), Gynipral enhances the oxidative activity of cells; at a high level of radical reaction of neutrophils (during the luteal phase of the cycle and after childbirth), Gynipral inhibits it. It can be assumed that in women, catecholamines (adrenaline) during pregnancy through β2- and/or β3-adrenergic receptors increase the ability of neutrophils to produce activated forms of oxygen, while after delivery they reduce this ability. Such changes in receptor activation may be associated with the phenomenon of switching of β-adrenergic receptor coupling from Gs protein to Gi protein, which is important for regulatory mechanisms. For citation: Polezhaeva T.V., Paturova I.G., Zaytseva O.O., Solomina O.N., Khudyakov A.N., Sergushkina M.I., Dmitrieva S.L., Tsirkin V.I. Effect of Beta-Adrenergic Agonist Gynipral on the Radical Activity of Neutrophils in the Blood of Women at Different Stages of Reproduction. Journal of Medical and Biological Research, 2021, vol. 9, no. 2, pp. 171–181. DOI: 10.37482/2687-1491-Z055

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.

For the first time, the effect of mechanocomposite (MC) based on biogenic silica and green-tea catechins on axillary shoot formation, physiological and biochemical characteristics of two strawberry cultivars (‘Alpha’ and ‘Solnechnaya polyanka’) was studied. The shoots were cultured on Gamborg-Eveleg’s medium (B5) supplemented with 0.75 mg l−1 6-benzylaminopurine (BA) (control) and 0.0, 2.5, 5.0 or 10.0 mg l−1 MC for 60 days. The highest regeneration responses (100%) and axillary shoot proliferation (up to 15.06 ± 0.81) correlating with increasing fresh weight (FW), dry weight (DW) on the media supplemented with 5.0 mg l−1 MC for both genotypes were recorded. The improvement in shoot regeneration accompanied with enhancing some antioxidant enzymes activity (superoxide dismutase and peroxidase) on the media supplemented with 5.0 mg l−1 MC for both genotypes. The increase in endogenous H2O2 concentration displaying a high morphogenetic potential in the presence of 2.5 and 5.0 mg l−1 MC was only observed in cv. ‘Alpha’ shoots. Overall, a positive effect of MC on the quality of in vitro shoots was established. Concentrations of photosynthetic pigments (chlorophylls a and b, and carotenoids), and their ratios (chlorophyll a/b, chlorophyll (a + b)/carotenoids) indicated a high physiological state of the plantlets grown with 5.0 mg l−1 MC. The accumulation of endogenous cytokinin (iP) and indole-3-acetic acid (IAA) is associated with the effect of MC in various concentrations on the organogenic response of both cultivars. Thus, the outcomes of this study can be utilized for the development of new systems for a healthy planting material production using “green chemistry” approaches and recommended for commercial strawberry micropropagation. Silicon chelates from plant waste are the useful component of plant tissue culture media for optimizing commercial strawberry micropropagation and preventing the occurrence of in vitro-derived disorders in plantlets.

This paper reviews the foraminiferal biostratigraphy of the Devonian–Carboniferous (D–C) boundary beds in Russia and Western Kazakhstan. The regional records of the zonal successions of Russia are summarised from sections and boreholes of the Volga-Urals Subregion of the East European Platform (Syzran no. 401 Borehole, Melekesskaya no.1 Borehole); Timan-Pechora Province of the East European Platform (Kamenka Section); South Urals (Sikaza, Zigan, Ryauzyak and Dzerzhinka sections); Middle Urals (Pershino Section); and West Siberia, Vagai-Ishim Basin (Borehole no. 1 Kurgan-Uspenskaya), and the zonal successions of Western Kazakhstan are summarised from the Mugodzhary Mountains. Three foraminiferal biozones can be defined in the interval comprising the latest Devonian and earliest Carboniferous: Quasiendothyra kobeitusana Zone, the Tournayellina pseudobeata – remnant Quasiendothyra Zone, and the Earlandia minima Zone. The D–C boundary interval is situated within the Tournayellina pseudobeata–remnant Quasiendothyra Zone. A correlation with the ammonoid and conodont zonations is proposed, which is useful for correlating deep-water and shallow-water successions.

The effect of heavy-metal ions (Cd2+, Cr6+, and Cu2+) on cyanobacteria sp. Microcystis and sp. Synechocystis has been studied. Since heavy metals impact causes blocking of light-energy transmission channels and arrest of electron transport in photosynthetic apparatus of cyanobacteria, their influence can be detected within a few hours by fluorescence techniques. In this investigation three standard fluorescence techniques are used: fluorescence spectroscopy, pulsed amplitude modulation fluorimetry, and confocal microscopic spectroscopy. All three used methods showed a decrease in photosynthetic activity for cyanobacterial cells exposed to heavy metals. However, the mechanisms of action for different heavy metals are slightly different. In this paper, we analyze variations in spectroscopic and kinetic properties of emmitted fluorescence for cyanobacterial cultures and single living cells in order to identify a specific mechanism of heavy metals influence.

When studying the formation of secondary metabolites represented by phenolic compounds in callus cultures of sunflower plants, it was found that in vitro under the influence of a stress factor, the accumulation of polyphenols increases. It was found that the biosynthetic activity of callus cultures in relation to polyphenols increases in proportion to the concentration of the mushroom culture filtrate Sclerotinia sclerotiorum in the nutrient medium.

As was shown earlier, in some hibernating rodents the patterns of hibernation are recorded by tooth dentine and can be revealed in stained or ground sections of the incisors, as well as on the incisor surface. Hibernation in the common hamster, Cricetus cricetus, can be described as facultative with great individual variability of the body temperature dynamics during the winter. To investigate the records of hibernation on the incisor surface of this species, we studied the lower incisors of hamsters that had wintered with implanted temperature data loggers under natural conditions in a city park of Simferopol, Crimea (two animals); in semi-natural conditions in the village of Khunzakh, Dagestan (two animals); and using 19 hamsters from a natural population found dead in Simpferopol or its environs during late winter or early spring. Previous studies of eight hamsters that were kept under laboratory conditions and that had received tetracycline injections confirmed the daily formation of the increments on the incisor surface. This data allowed us to find the part of the incisor that could have been formed during hibernation in the hamsters with implanted loggers. In three of four of them, the typical pattern of daily increments was disrupted in the parts presumably formed during hibernation. The patterns of disruption varied in different animals, and it was impossible to interpret them as a record of hibernation. Those hamsters revealed no sequences of narrow and clearer increments characteristic of the records of hibernation on incisors. Such a sequence was seen on incisors of only one of 19 hamsters from the natural population. Consequently, no unambiguous record of the periods of hypothermia was found on the surface of incisors in the common hamster. According to the data published earlier, hibernation records on incisors were found in other hamsters of the subfamily Cricetinae (the genera Allocricetulus and Mesocricetus, in particular). A comparison of the dynamics of body temperature during hibernation in these hamsters and in the common hamster allow us to surmise that the formation of narrow increments can be determined in part by the depth and duration of hypothermia, but it mainly depends on the duration of normothermia and the feeding habits of animals during hibernation.

The qualitative composition of the most important biologically active lipid substances-carotenoids and chlorophyll derivatives of the White sea algaeSaccharina latissimahas been studied. The lipid extract was separated by thin-layer chromatography (TLC) and examined by matrix-associated laser desorption-ionization with mass-spectrometric analysis (MALDI-MS). The extract contained fucoxanthin, fucoxanthinol, pheophytin a, pheophorbide a, as well as other carotenoids and chlorophylls, including those not described in the literature. The results obtained, which significantly expand the information about the composition of S. latissima pigments, can be used to standardize raw materials and preparations based on these algae.

Background. Lodging has an extremely negative impact on barley yield: grain quality and planting properties are deteriorated, disease incidence increases, and mechanized harvesting becomes difficult, so it is important to find new sources of lodging resistance in barley and use them in crosses and breeding programs to develop non-lodging barley cultivars.Materials and methods. Experimental work was carried out in 2018 and 2019 at Federal Agricultural Science Center of the North-East (FASC North-East), Kirov. Yield structure components and lodging resistance levels were assessed for 29 accessions from the spring barley collection. The study was based on the International COMECON List of Descriptors for the Genus Hordeum L. (subgen. Hordeum) and Methodological Guidelines for the Study and Preservation of the World Collection of Barley and Oats.Results and conclusions. Lodging resistance was observed to have a strong correlation with yield (r = 0.72) and plant height (r = –0.60), and a medium correlation with tillering (r = 0.40) and number of nodal roots at maturation (r = 0.44). No relationship was found between lodging resistance and morphological features of the second lowest internode, which means that selection of non-lodging forms by these criteria will not be effective. Lodging-resistant accessions demonstrated higher yield, tillering, productivity, 1000 grain weight, and a longer and denser ear compared to nonresistant accessions. Accessions combining high yield with lodging resistance and a set of traits promising for breeding were identified: ‘Belgorodsky 100’, ‘Naran’ (k-30892), ‘Kazminsky’ (k-30926), ‘Shchedry’ (k-31046) (Russia); ‘Syabra’ (k-30917), ‘Raider’ (Belarus); ‘Odesssky 115’ (k-29010, Ukraine), ‘Mie’ (k-30379, Estonia), ‘Rodos’ (k-30256, Poland).

Assessment of the acute toxicity, safety and biological activity of lipophilic extracts of the White Sea brown algae“– S. latissima and F. vesiculosus– on the model of zoohydrobionts Daphnia magna Straus has been performed.Two methods of obtaining dry lipid concentrate of kelp and fucus were tested. It has been shown that the acute toxicity of the lipid extract of kelp does not depend on the method of its preparation and is about 200 mg/L. The acute toxicity of fucus extract depends on the method of preparation. It is about 100 mg/L in the «cold» method of extraction and increases by an order of magnitude in the «hot» method. To study the biological activity, samples of brown algae obtained by «cold» extraction were used.In chronic experiments, preparations of brown algae were used in a concentration of 8.0 mg/L, which was less than 0,1 LC50 of the acute toxicity of fucus and did not cause toxic effects.For 24 days, the preparations were introduced in contact with Daphnia twice a week. Subsequently, the control and experimental hydrobionts were kept under the same conditions until the death of the last individuals. It has been shown that the preparations of S. latissima and F. vesiculosus in the proposed concentration by 20-30% increased the lifespan of Daphnia in normal conditions and by 50-60% in extreme conditions, while stimulating the reproductive activity of aquatic organisms by 3-4 times. The results obtained suggest that the studied drugs have pronounced adaptogenic and cytoprotective effects.

Background. The efficiency of breeding depends largely on the breeding method and the choice of the source material. Hybridization and mutagenesis, combined with selection, are the basic techniques in the development of promising breeding materials and adaptable cultivars of spring barley.Object and methods. The research was implemented in 2002–2019. The material for the research were 948 breeding lines (Federal Agricultural Science Center of the North-East, Kirov) developed through hybridization with cv. ‘Bios 1’, and 190 mutant samples (Vyatka State Agricultural Academy, Kirov) obtained as a result of treating barley seeds with sodium carbonate and irradiation with laser and far-red light in various combinations. The study was conducted in accordance with approved standard techniques.Results and conclusions. Various collection accessions and breeding lines were involved in crosses with cv. ‘Bios 1’. The lines were studied according to the full-scale scheme of the breeding process. As a result, only one breeding line, 52-15, having ‘Bios 1’ in its pedigree, was approved for testing in the competitive variety trial in 2019. These results attested to a low combination capacity of cv. ‘Bios 1’ and to the inefficiency of its further use in hybridization as a parent form. In Vyatka State Agricultural Academy, 190 mutant forms of barley were produced using ‘Bios 1’ as the initial form. According to the results of laboratory experiments and competitive variety trials, 5 mutant forms of barley were identified as promising. Spring barley samples, combining high yield with a set of traits valuable for breeding, were selected for further breeding work: breeding line 52-15, and mutant forms M 4-16-3, M 9-5-3 and M 11- 13 Kha. The new barley accession M 8-3-013, maturing 8 days earlier than the original cultivar, having a long (8.9 cm), wellgrained (24.3 grains) and productive (1.31 g) ear, is submitted for the State Variety Trials.

In order to induce in vitro axillary shoot proliferation from single-node explants of Rhododendron mucronulatum Turcz., two techniques of thidiazuron (TDZ) application were tested: (i) two-step procedure including cultivation on Anderson medium (AM) supplemented with varying TDZ concentrations (0.1 μM; 0.25 μM; 0.5 μM; 1.0 μM; 2.5 μM) for 8 wk followed by cultivation on hormone-free medium (AM0) for 6 wk and (ii) 4-h liquid-pulse treatment with different TDZ concentrations (7.5 μM, 15.0 μM, or 30.0 μM) followed by cultivation on AM0 for 8 wk. The highest number of axillary shoots per explant was achieved with 0.1-μM TDZ after the two-step procedure. The best response in terms of percent regeneration (87%), shoot length (13 mm), absence of structure anomalies, and the shortest shoot production cycle (8 wk) was obtained with 30.0-μM TDZ liquid-pulse treatment for 4 h. The clonal fidelity of regenerated shoots was evaluated by random amplified polymorphic DNA (RAPD) and inter-simple sequence repeats (ISSR) markers and flow cytometry. Genetic similarity of all regenerants between themselves and with the mother seedlings was 99%. Flow cytometric analysis revealed that all samples studied were diploid. The nuclear DNA content of microshoots obtained under the TDZ treatments varied from 1.26 to 1.32 pg per 2C. There were no significant differences in DNA content among mother seedlings and in vitro developed shoots triggered by 0.1- and 2.5-μM TDZ nor by those triggered by the 30.0-μM TDZ pulse treatment.

Age-related changes in telomere length (TL) in somatic tissues are not limited only to shortening. It is known that many organisms show different TL dynamics. Such species specificity indicates the complexity of the mechanisms involved in the regulation of TL. Owing to their morphological, physiological, and ecological features, Baikal planarians are an interesting model for studying the TL dynamics and the factors influencing it in comparison with species living outside Baikal. In this work, we investigated telomerase activity and age-related changes in TL in three endemic species of planarians from the Dendrocoelidae family. Two species are giant deep-water species (7-12 cm long, Sorocelis hepatizon and Rimacephalus arecepta), and one is a coastal shallow species (1 cm long, Baikalobia guttata). In addition, we investigated the telomere biology in another small Siberian species from the Planariidae family (2 cm in length, Phagocata sibirica), which is not found in Baikal. TL and telomerase activity were determined using real-time PCR and the TRAP method. Three types of age-related TL dynamics were detected with active telomerase: (1) TL shortening at the juvenile stage of development and subsequent maintenance (R. arecepta, Ph. sibirica), (2) gradual TL shortening during ontogeny (S. hepatizon) and (3) cyclic dynamics of TL (B. guttata). Thus, the changes of TL in the studied planarians does not have an obvious connection with body size, habitat depth, phylogenetic relationship and is probably a consequence of species features in the regulation of telomerase activity.

T cell–directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)–interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5–IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5–IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a + NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5–IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ–inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a + CXCR6 + NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell–focused therapies and offer mechanistic insights into how T cell–NK cell–DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance.

Over 1,500 missense variants of sodium channel hNav1.5, which are reported in the ClinVar database, are associated with cardiac diseases. For most of the variants, the clinical significance is uncertain (VUS), not provided (NP), or has conflicting interpretations of pathogenicity (CIP). Reclassifying these variants as pathogenic/likely pathogenic (P/LP) variants is important for diagnosing genotyped patients. In our earlier work, several bioinformatics tools and paralogue annotation method consensually predicted that 74 VUS/NP/CIP variants of 54 wild type residues (set w54) are potentially damaging variants (PDVs). Atomic mechanisms underlying dysfunction of the PDVs are unknown. Here we employed a recent cryo-EM structure of the hNav1.5 channel with likely inactivated pore domain (PD) and activated voltage-sensing domains (VSDs), and ad hoc models of the closed and open PD and resting VSDs to explore intersegment contacts of w54 residues. We found that 44 residues from set w54 contact 84 residues with 118 disease missense variants. These include 104 VUS/NP/CIP variants, most of which are associated with the loss-of-function Brugada syndrome (BrS1) or gain-of-function long QT syndrome (LQT3). Matrix representation of the PDVs and their contact variants facilitated recognition of coupled mutations associated with the same disease. In particular, BrS1-associated coupled mutations, which disturb the P-loops region with the selectivity filter slow inactivation gate, would cause the channel dysfunction. Other likely causes of the channel dysfunction include coupled BrS1-associated variants within VSDs that would destabilize their activated states and coupled LQT3-associated variants, which would stabilize the open PD or activated VSDs. Our study proposes mechanisms of channel dysfunction for scores of BrS1- and LQT3-associated variants, confirms status for 82% of PDVs, and suggests damaging status for their contact variants, which are currently categorized as VUS/NP/CIP variants.

Summary Systemic lupus erythematosus (SLE) is characterized by a loss of self-tolerance, systemic inflammation, and multi-organ damage. While a variety of therapeutic interventions are available, it has become clear that an early diagnosis and treatment may be key to achieve long lasting therapeutic responses and to limit irreversible organ damage. Loss of humoral tolerance including the appearance of self-reactive antibodies can be detected years before the actual onset of the clinical autoimmune disease, representing a potential early point of intervention. Not much is known, however, about how and to what extent this pre-phase of disease impacts the onset and development of subsequent autoimmunity. By targeting the B cell compartment in the pre-disease phase of a spontaneous mouse model of SLE we now show, that resetting the humoral immune system during the clinically unapparent phase of the disease globally alters immune homeostasis delaying the downstream development of systemic autoimmunity., Graphical abstract, Highlights • The clinically unapparent pre-phase of SLE impacts clinical disease • Autoreactive IgM antibodies represent a biomarker for early therapeutic intervention • Pre-phase B cells orchestrate clinical disease • Depleting pre-phase B cells diminishes disease pathology, Biological sciences; Immune system disorder; Immune response.

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. During long-term potentiation and synaptic upscaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to phosphorylation of AMPAR subunit GluA1 (also known as GRIA1) and subsequent elevation of GluA1 surface expression, either by an increase in receptor forward trafficking to the synaptic membrane or a decrease in receptor internalization. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 serine 845 (S845) predominantly plays a role in receptor internalization, rather than forward trafficking, during synaptic plasticity. Notably, internalization of AMPARs depends upon the clathrin adaptor AP2, which recruits cargo proteins into endocytic clathrin-coated pits. In fact, we further reveal that an increase in GluA1 S845 phosphorylation upon two distinct forms of synaptic plasticity diminishes the binding of the AP2 adaptor, reducing internalization and resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated internalization of AMPARs.

Quorum Sensing (QS) is a mechanism of bacterial intercellular communication that depends on their population density. QS activates the expression of hundreds of bacterial genes, many of which play an important role in plant-bacterial interactions. This review summarizes the latest achievements in the research of bacterial QS signaling in plant-microbial interactions. The review focuses specifically on the best-studied QS systems, i.e., those of gram-negative bacteria which involve N-acyl-homoserine lactones (AHL). The effects of AHL and AHL-producing bacteria on plant growth, development, and defense responses are considered. Signaling functions of plant metabolites which regulate QS-dependent behavior of associated microbiota via the activation or inhibition of bacterial QS systems are described. Possible degradation pathways of AHL in the rhizosphere are also considered. Practical applications of QS regulation for plant protection are discussed.

Mutations in gene SCN5A, which encodes cardiac voltage-gated sodium channel Nav1.5, are associated with multiple clinical phenotypes. Here we describe a novel A1294G genetic variant detected in a male patient with combined clinical phenotype including atrioventricular II block, Brugada-like ECG, septal fibrosis, right ventricular dilatation and decreased left ventricular contractility. Residue A1294 is located in the IIIS3-S4 extracellular loop, in proximity to several residues whose mutations are associated with sodium channelopathies. The wild-type channel Nav1.5 and mutant Nav1.5-A1294G were expressed in the CHO-K1 and HEK293T cells and whole-cell sodium currents were recorded using the patch-clamp method. The A1294G channels demonstrated a negative shift of steady-state inactivation, accelerated fast and slow inactivation and decelerated recovery from intermediate inactivation. Our study reveals biophysical mechanism of the Nav1.5-A1294G dysfunction, which may underlie the combined phenotypic manifestation observed in the patient.

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provides persistent signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking endocytosis or endosomal Met/β1-integrin/FAK signaling profoundly inhibits the oncogenic effects of both NRP1 variants. These findings reveal an important role for these NRP1 splice variants in the regulation of endocytic trafficking for cancer cell dissemination., O-glycosylation of neuropilin-1 is involved in cancer migration and invasion. Here, the authors show that defects in N-glycosylation of two neuropilin-1 splice variants enhance the co-internalisation of Met, it’s interaction with β1-integrin, and subsequent constitutive activation of FAK/p130Cas signalling in endosomes to promote colorectal cancer metastasis.

The removal of endocrine-disrupting xenobiotics, technical nonylphenol (NP) and 4-tert-octylphenol (OP), from aquatic environment by the cyanobacterium Planktothrix agardhii has been studied. It is shown that nonyl- and octylphenols are removed from aqueous medium in the presence of the cyanobacterium P. agardhii mainly via abiotic pathways—photolysis and hydrolysis—and biodegradation by cyanobacterial cells rather than by adsorption and accumulation in the cells. P. agardhii has a higher destructive and sorption ability for nonylphenol compared to octylphenol. The results indicate the possibility of self-purification of water bodies contaminated with alkylphenols with the participation of the mass species of cyanobacteria Planktothrix agardhii.

Conodonts, scolecodonts, and foraminifers from the Frasnian Age (Upper Devonian) (Shchigry-16 borehole, Nizhnekrasnoe village, Voronezh anteclise) were studied. Six conodont assemblages were identified: I for the Timan regional stage, II and III for the Sargaevo regional stage, and IV–VI for the Semiluky regional stage. These assemblages were correlated with local zonal subdivisions and the Standard Conodont Zonation. It was established that a shallow-water environment was characteristic of the Timan regional stage; the deepest environment was characteristic of the Semiluky regional stage. Five scolecodont assemblages were identified: 1 and 2 in the Sargaevo regional stage, 3 and 4 in the Semiluky regional stage, and 5 in the upper part of Semiluky and Voronezh regional stages. Two foraminiferal assemblages are distinguished for the Sargaevo and Semiluky regional stages. The characteristic microfossils species are given in plates.

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance.SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrichtumors, resistance to IL-12 or anti-PD-1 in trNK cellpoortumors can be overcome by the additional delivery of CCL5.

Interspecific facilitation between ecosystem engineers, such as salt marsh grass and mussel aggregations, is a key process that structures communities and enhances biodiversity. Scale-dependent pattern formation via self-organization is ubiquitous in terrestrial, aquatic and marine ecosystems. Despite their prevalence and ecological importance, these two phenomena have rarely been linked. We provide empirical evidence that the facilitative interaction in salt marshes between smooth cordgrassSpartina alternifloraand the ribbed musselGeukensia demissaproduces distinct spatial patterns along marsh shorelines. These findings advance our understanding of linkages between facilitation and pattern formation in nature, and are particularly relevant to conservation and restoration of salt marshes threatened by climate change and sea-level rise.

Among Gerbillinae rodents, ultrasonic calls of adults of small-sized species are typically higher frequency than those of adults of large-sized species. This study investigates whether a similar relationship can be found in pups of six gerbil species ( Dipodillus campestris , Gerbillus perpallidus , Meriones unguiculatus , Meriones vinogradovi , Sekeetamys calurus and Pachyuromys duprasi ). We compared the average values of acoustic variables (duration, fundamental and peak frequency) of ultrasonic calls (20 calls per pup, 1200 in total) recorded from 6- to 10-day-old pups (10 pups per species, 60 in total) isolated for 2 min at 22°C and then weighed and measured for body variables. The longest calls (56 ± 33 ms) were found in the largest species, and the highest frequency calls (74.8 ± 5.59 kHz) were found in the smallest species. However, across species, call duration (ranging from 56 to 159 ms among species) did not display a significant relationship with pup body size; and, among frequency variables, only the minimum fundamental frequency depended on pup body size. Discriminant analysis assigned 100% of calls to the correct species. The effect of species identity on the acoustics was stronger than the effect of body size. We discuss these results with the hypotheses of acoustic adaptation, social complexity, hearing ranges and phylogeny.

Rhizosphere bacteria are considered to be promising destructors of oil and its components. Bacterial species of the genus Rhodococcus can degrade a variety of hydrocarbons and are widely used for the bioremediation of polluted environments. Here, we report the complete genome sequence of Rhodococcus qingshengii strain VKM Ac-2784D.

Monohydrocalcite (CaCO3·H2O) is a mineral rarely found in natural environments. Here we report finding of this mineral in the composition of the microbialites in Laguna de los Cisnes (Isla Grande, Chile), a saline alkaline lake with high Mg/Ca ratio. We have made a detailed structural and mineralogical description of these microbialites with the use of light and scanning electron microscopy, infrared spectroscopy and X-ray analysis. The predominantly carbonate composition of microbialites was revealed. Carbonates were represented mainly by high-magnesium calcites and monohydrocalcite. Calcite and aragonite were found in minor quantities. In addition, a small amount of silicates and amorphous hydromagnesite were found. The yellowish-brown surface layer of microbialites consists of numerous crystals within a mineralized exopolysaccharide (EPS) matrix. A large number of unicellular and filamentous algae, as well as areas of released EPS, are also seen here. Below is a slimy green layer. This layer is not mineralized, it represents an "algal-bacterial mat" consisting of algae, cyanobacteria, and diatoms developed in EPS. Chisel-shaped crystals of monohydrocalcite and its amorphous spherical precursors are numerous in these upper layers. The deeper layers are mineralized, they consist predominantly of Mg-carbonates with varying degrees of Mg. Algae and cyanobacteria are decomposed or fossilized there. Thus, monohydrocalcite occurs in the composition of the microbialites being one of the main mineral components. As in other lacustrine localities it is formed in the presence of algae and cyanobacteria. To our knowledge this is the first report on the discovery of monohydrocalcite in South America.

Simple Summary The microalga Haematococcus lacustris is a source of the natural colorant astaxanthin, a powerful antioxidant and key component of cosmetics and animal feed. Haematococcus is cultivated in photobioreactors. It can obtain energy just from a light illuminating photobioreactor and uses inorganic salts and CO2 as sources for chemical elements. The most widespread approach for Haematococcus cultivation is the two stage scheme. At the first stage, biomass accumulation under favorable growth conditions occurs. At the second stage, the cells are subjected to stress inducing astaxanthin synthesis. Generally, the culture of Haematococcus is not axenic. It exists in the form of a community with bacteria constituting its microbiome. The information on photobioreactor-cultivated Haematococcus microbiome is scarce. We analyzed its dynamic during astaxanthin production by DNA metabarcoding and microscopic observations. The main results of the work include the characterization of the daily dynamic of this microbiome and the revealing of contact between microalgae and bacteria. These findings are of potential significance for biotechnology. On one hand, they provide an insight into possible bacterial contamination of the harvested algal biomass. On the other hand, they reveal the presence of a core microbiome or bacteria essential for the growth of the microalga existing in all Haematococcus cultures. Abstract Haematococcus lacustris is a natural source of a valuable ketocarotenoid astaxanthin. Under autotrophic growth conditions, it exists in the form of a community with bacteria. The close coexistence of these microorganisms raises two questions: how broad their diversity is and how they interact with the microalga. Despite the importance these issues, little is known about microorganisms existing in Haematococcus cultures. For the first time, we characterize the dynamic of the H. lacustris microbiome of the microbiome of Haematococcus (a changeover of the bacterial associated species as function of the time) cultivated autotrophically in a photobioreactor based on 16S rRNA metabarcoding data. We found that Proteobacteria and Bacteroidetes are predominant phyla in the community. The Caulobacter bacterium became abundant during astaxanthin accumulation. These data were supported by microscopy. We discuss possible roles and interactions of the community members. These findings are of potential significance for biotechnology. They provide an insight into possible bacterial contamination in algal biomass and reveal the presence of bacteria essential for the algal growth.

Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, N-glycosylation biosynthesis is not a template-driven process, but rather a complex process regulated by both genetic and environmental factors. Current heritability studies have shown that while up to 75% of the variation in levels of some IgG glycan traits can be explained by genetics, some glycan traits are completely defined by environmental influences. Advances in both high-throughput genotyping and glycan quantification methods have enabled genome-wide association studies that are increasingly used to estimate associations of millions of single-nucleotide polymorphisms and glycosylation traits. Using this method, 18 genomic regions have so far been robustly associated with IgG N-glycosylation, discovering associations with genes encoding glycosyltransferases, but also transcription factors, co-factors, membrane transporters and other genes with no apparent role in IgG glycosylation. Further computational analyses have shown that IgG glycosylation is likely to be regulated through the expression of glycosyltransferases, but have also for the first time suggested which transcription factors are involved in the process. Moreover, it was also shown that IgG glycosylation and inflammatory diseases share common underlying causal genetic variants, suggesting that studying genetic regulation of IgG glycosylation helps not only to better understand this complex process but can also contribute to understanding why glycans are changed in disease. However, further studies are needed to unravel whether changes in IgG glycosylation are causing these diseases or the changes in the glycome are caused by the disease.

Gymnadenia conopsea (Fragrant orchid) is a widespread model species for the study of polymorphism in the European part of Russia and abroad. Flow cytometry refers to rapid methods effective for assessing the structure of a population by DNA size estimation. However, this method is only available in habitats with close proximity to the place of the experiment, because this indicator is determined only in fresh leaves. A small population of G. conopsea in the industrial area adjacent to the Novosibirsk urban agglomeration in the Novosibirsk Region (NR) was studied. Only diploids were detected in the G. conopsea cenopopulation occurred in the industrial zone of the NR. In this study we pointed on significance of genome size variation, which correlates with the adaptive evolution of the G. conopsea in West Siberia. The revealed absence of minor cytotypes (individuals with a higher level of ploidy) in G. conopsea population reduces intraspecific and intrapopulation diversity of the species.

Discoveries of new plant growth regulators are significantly enriching the range of tools used by researchers in plant tissue culture. Meta-topolin (mT, 6-(3-hydroxybenzylamino) purine), firstly isolated from poplar leaves, is a highly active natural aromatic cytokinin successfully used over the last two decades in many different biological fields. The main criteria of its efficiency in plant micropropagation are high multiplication rate, shoot health, good rooting, and acclimatization ability. The absence of abnormalities and somaclonal variation are further advantages. For this reason, mT is examined in various regeneration systems in comparison with isoprenoid, aromatic, as well as phenylurea derivatives with cytokinin-like activity. This chapter will review the advantages and disadvantages of mT application as an inducer of different morphogenetic pathways of plant regeneration in vitro, including axillary shoot proliferation, de novo organogenesis, and somatic embryogenesis.

The application of both fluorescence and electron microscopy results in a powerful combination of imaging modalities called "correlative light and electron microscopy" (CLEM). Whereas conventional transmission electron microscopy (TEM) tomography is only able to image sections up to a thickness of ~300nm, scanning transmission electron microscopy (STEM) tomography at 200kV allows the analysis of sections up to a thickness of 900nm in three dimensions. In the current study we have successfully integrated STEM tomography into CLEM as demonstrated for human retinal pigment epithelial 1 (RPE1) cells expressing various fluorescent fusion proteins which were high-pressure frozen and then embedded in Lowicryl HM20. Fluorescently labeled gold nanoparticles were applied onto resin sections and imaged by fluorescence and electron microscopy. STEM tomograms were recorded at regions of interest, and overlays were generated using the eC-CLEM software package. Through the nuclear staining of living cells, the use of fluorescently labeled gold fiducials for the generation of overlays, and the integration of STEM tomography we have markedly extended the application of the Kukulski protocol (Kukulski et al., 2011, 2012). Various fluorescently tagged proteins localizing to different cellular organelles could be assigned to their ultrastructural compartments. By combining STEM tomography with on-section CLEM, fluorescently tagged proteins can be localized in three-dimensional ultrastructural environments with a volume of at least 2.7×2.7×0.5μm.

The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.

The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC’s capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC’s roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.

The internal surface of the animal gastrointestinal tract is covered by microbial biofilms. They play an important role in the development and functioning of the host organism and protect it against pathogens. Microbial communities of gastrointestinal biofilms are less elucidated than luminal microbiota. Therefore, the studies of biofilm formation by gastrointestinal microorganisms are a topical issue. For the first time, we report the formation of a biofilm in vitro by the strains of bioluminescent bacteria isolated from the intestines of marine fish. These bacteria exhibit co-aggregation and tend to attach to solid surfaces. The attachment of cells is accompanied by appearance of the pili. Then, we observed the formation of microcolonies and the production of extracellular polymer substances (EPSs) connecting bacterial cells into an integrated system. The presence of acidic polysaccharides is shown in the EPS when using the ruthenium red staining. Acidic polysaccharides in this matrix is a biochemical evidence of microbial biofilms. On the fibers of the polymer matrix, these bacteria form the "mushroom body"-type structures. Matured biofilms exhibit a specific three-dimensional architecture with pores and channels formed by cells and EPS. We also demonstrated the formation of a biofilm by binary culture of the luminous enterobacterium Kosakonia cowanii and a Gram-positive Macrococcus sp. The data obtained help to understand the role of these bacteria in the intestines of fish. They lead to a new study in the field of investigation of the intestinal microbiome of fish.

Broad-spectrum antimicrobial peptides (AMPs) kill bacteria indiscriminately, increasing the possibility of an ecological imbalance in the microbiota. To solve this problem, new types of AMPs, which kill pathogenic bacteria without breaking the micro-ecological balance of the body, were proposed. Here, we successfully designed a targeting AMP, S2, which is a fusion peptide composed of a species-specific targeting domain and broad-spectrum AMP domain. In the current study, S2 showed specific killing activity against Staphylococcus aureus, and almost no resistance induced compared to penicillin. Mechanism studies indicated that S2 killed S. aureus by destroying the bacterial membrane. Meanwhile, S2 possessed excellent salt-tolerance properties and biocompatibility. Importantly, S2 exhibited perfect treatment efficacy against an S. aureus subcutaneous infection model and remained nontoxic. In conclusion, this study provides a promising strategy for designing specific AMPs against growing bacterial infections.

Fatty acid synthase, a key enzyme of de novo lipogenesis, is an attractive therapeutic target in cancer. The novel fatty acid synthase inhibitor, TVB-3664, shows anti-cancer activity in multiple cancers including colorectal cancer; however, it is unclear whether uptake of exogeneous fatty acids can compensate for the effect of fatty acid synthase inhibition. This study demonstrates that inhibition of fatty acid synthase selectively upregulates fatty acid translocase (CD36), a fatty acid transporter, in multiple colorectal cancer models including colorectal cancer cells with shRNA mediated knockdown of fatty acid synthase and genetically modified mouse tissues with heterozygous and homozygous deletion of fatty acid synthase. Furthermore, human colorectal cancer tissues treated with TVB-3664 show a significant and selective upregulation of CD36 mRNA. shRNA-mediated knockdown of CD36 and inhibition of CD36 via sulfosuccinimidyl oleate, a chemical inhibitor of CD36, decreased cell proliferation in vitro and reduced tumor growth in subcutaneous xenograft models. Isogenic cell populations established from patient derived xenografts and expressing high levels of CD36 show a significantly increased ability to grow tumors in vivo. The tumor-promoting effect of CD36 is associated with an increase in the levels of pAkt and survivin. Importantly, combinatorial treatment of primary and established colorectal cancer cells with TVB-3664 and sulfosuccinimidyl oleate shows a synergistic effect on cell proliferation. In summary, our study demonstrates that upregulation of CD36 expression is a potential compensatory mechanism for fatty acid synthase inhibition and that inhibition of CD36 can improve the efficacy of fatty acid synthase-targeted therapy.

Background/aims Mutations of desmosomal genes are known to cause arrhythmogenic cardiomyopathy characterized by arrhythmias and sudden cardiac death. Previously, we described a novel genetic variant H1684R in desmoplakin gene (DSP), associated with a progressive cardiac conduction disease (PCCD). In the present study, we aimed to investigate an effect of the DSP-H1684R genetic variant on the activity of ion channels. Methods We used cardiomyocytes derived from induced pluripotent stem cells (iPSC cardiomyocytes) from a patient with DSP-H1684R genetic variant and from two healthy donors. Immunofluorescent staining and western blot analyses were used to characterize patient-specific cardiomyocytes. By the whole-cell voltage-clamp technique we estimated the activity of voltage-gated sodium, calcium, and potassium channels that are responsible for action potential generation and its shape. Action potentials' parameters were measured using whole-cell current-clamp technique. Results In patient-specific cardiomyocytes we observed both lower amplitudes of currents through sodium Nav1.5 channels and L-type calcium channels, but higher amplitude of current through transient-outward potassium channels in comparison to donor cardiomyocytes. Current-clamp measurements revealed shortening of action-potential in DSP-H1684R-carrying iPSC cardiomyocytes. Therefore, observed alterations in the channels activity might have a great impact on the properties of action potential and development of PCCD. Conclusion Our results show that desmoplakin genetic variants, besides conduction slowing caused by structural heart remodeling, could affect multiple ion channel activity aggravating arrhythmia manifestation in PCCD.

Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC., Polyamine metabolism is frequently dysregulated in cancers. Here, the authors show that a polyamine biosynthetic enzyme, spermine synthase, is overexpressed in colorectal cancers and cooperates with MYC to prevent cancer cell apoptosis by repression of proapoptotic protein, Bim.

Here, we report novel tumour suppressor activity for the Drosophila Argonaute family RNA-binding protein AGO1, a component of the miRNA-dependent RNA-induced silencing complex (RISC). The mechanism for growth inhibition does not, however, involve canonical roles as part of the RISC; rather, AGO1 controls cell and tissue growth by functioning as a direct transcriptional repressor of the master regulator of growth, Myc. AGO1 depletion in wing imaginal discs drives a significant increase in ribosome biogenesis, nucleolar expansion and cell growth in a manner dependent on Myc abundance. Moreover, increased Myc promoter activity and elevated Myc mRNA in AGO1-depleted animals requires RNA polymerase II transcription. Further support for transcriptional AGO1 functions is provided by physical interaction with the RNA polymerase II transcriptional machinery (chromatin remodelling factors and Mediator Complex), punctate nuclear localisation in euchromatic regions and overlap with Polycomb Group transcriptional silencing loci. Moreover, significant AGO1 enrichment is observed on the Myc promoter and AGO1 interacts with the Myc transcriptional activator Psi. Together, our data show that Drosophila AGO1 functions outside of the RISC to repress Myc transcription and inhibit developmental cell and tissue growth. This article has an associated ‘The people behind the papers’ interview.

Psi, the sole FUSE Binding Protein (FUBP) family single stranded DNA/RNA binding protein inDrosophila, is essential for proper cell and tissue growth, however its mechanism of function remains unclear. Here we use Targeted DamID combined with RNA-sequencing to generate the first genome-wide binding and expression profiles for Psi. Surprisingly, we demonstrate Psi drives growth in theDrosophilawing through transcriptional repression of key developmental pathways (e.g. Wnt, Notch and TGFβ). Thus, Psi patterns tissue growth by directly repressing transcription of developmental growth suppressors. Analysis of direct Psi targets identified novel growth inhibitors, includingTolkin(Zinc metallopeptidase implicated in TGFβ signalling),Ephexin(Rho-GEF) andemp(CD36 scavenger receptor-related protein). Their depletion not only suppressed impaired growth associated with Psi knockdown, but alone was sufficient to drive wing overgrowth. Thus, Psi drives wing growth twofold, through direct activation ofMycand through transcriptional repression of growth inhibitors comprising core developmental pathways.

Ontogeny of audible and ultrasonic calls is poorly studied in Gerbillinae rodents. In this study, analysis of calls, emitted by pup and adult fat-tailed gerbils Pachyuromys duprasi during 420-s isolation-and-handling procedures, allowed testing two hypotheses. Hypothesis1 predicted that audible squeaks and clicks follow the same ontogenetic pathway (towards higher-frequency and shorter calls) that has been previously documented for the ultrasonic calls of fat-tailed gerbil. Hypothesis2 predicted that the audible call types would alternate with the ultrasonic call types along ontogeny in this species. Hypothesis1 was tested with comparison of acoustic variables of audible calls (squeaks and clicks), emitted by 1-10-day old pups and by adults. Clicks of 8.3-8.7 kHz and high-frequency squeaks of 1.92-3.57 kHz were present in pups and adults, whereas mid-frequency squeaks of 0.31-0.67 kHz and low-frequency squeaks of 0.04-0.11 kHz were only present in pups. In agreement with Hypothesis1, pup high-frequency squeaks were longer, lower in fundamental frequency and higher in peak frequency. Against predictions, clicks did not differ acoustically between pups and adults. Hypothesis2 was tested with comparison of percentages of test trials containing the audible and/or ultrasonic call types of pups, repeatedly tested in 15 age classes along ontogeny from 1 to 40 days of age and in adults. The audible calls occurred in all age classes, whereas the ultrasonic calls emerged from day five of pup life and then prevailed over the audible squeaks in all age classes. We discuss that, in fat-tailed gerbil, ontogenetic pathways of acoustic variables of audible and ultrasonic calls (towards higher-frequency and shorter calls) are unusual for rodents although are typical for social and echolocation calls of bats. The is another parallelism of acoustic communication between bats and rodents aside from the recently discovered similarity between bat ultrasonic echolocation and echo-based navigation with bouts of ultrasonic calls in blind leaping rodents.

Show the possibilities of diagnosing non - tuberculous mycobacteriosis of the lungs (NTML) in the practice of the pulmonologist.A survey of 90 patients with a confirmed diagnosis of non - tuberculous mycobacteriosis of the lungs (NTML) was presented. The diagnosis of pulmonary mycobacteriosis was established in accordance with the criteria proposed in 2007 by the American Thoracic Society and the American Society of Infectious Diseases (ATS/IDRS). Among the patients, 55 (61.1%) women prevailed, the average age was 51.2±15.3 years. Patients were evaluated complaints, the presence of concomitant diseases of the lungs, was carried out computed tomography of the chest high - resolution (HRCT), a culture study of sputum, in the absence of sputum or a single determination of the NTM culture in it, a study was conducted on materials of bronchoalveolar washout (ALS/BAL), or lung biopsies. Statistical processing of the research results was performed using descriptive statistics using Microsoft® Excel for Windows xp® on a personal computer.As a result of the study, it was revealed that before the diagnosis of NTML was established, 66.7% of patients were long observed for chronic lung diseases (chronic obstructive pulmonary disease, chronic bronchitis), and in 55.6% of cases (50 people) were registered with a phthisiologist about pulmonary tuberculosis. According to the CT scan of OGK, dissemination was determined in 66.7% of cases, in 48.9% - bronchiectasis, single or multiple destruction cavities - 46.7% of cases. In 72.2% of cases, non - tuberculous mycobacteria (NTM) were found in sputum, in 33.3% - in ALS and in 22.2% of NTMs were found in the surgical material. In 14.4% of cases, only surgery allowed to establish the diagnosis of mycobacteriosis.Цель исследования. Показать возможности диагностики нетуберкулезных микобактериозов легких (НТМЛ) в практике пульмонолога. Материалы и методы. Представлены материалы обследования 90 пациентов с подтвержденным диагнозом НТМЛ. Диагноз микобактериоза легких установлен в соответствии с предложенными в 2007 г. критериями Американского торакального общества и Американского общества инфекционных болезней (ATS/IDRS). Среди пациентов преобладали женщины - 55 (61,1%) человек, средний возраст составил 51,2±15,3 года. У пациентов оценивали жалобы, наличие сопутствующих заболеваний легких, проводили компьютерную томографию высокого разрешения органов грудной клетки (КТ ОГК), культуральное исследование мокроты, в случае отсутствия мокроты или однократного определения в ней культуры нетуберкулезных микобактерий (НТМБ) проводилось исследование материалов бронхоальвеолярного смыва (БАС/БАЛ) или биоптатов легких. Статистическая обработка результатов исследования выполнена методом описательной статистики с использованием Microsoft® Excel для Windows хр® на персональном компьютере. Результаты и заключение. В результате проведенного исследования выявлено, что до установления диагноза НТМЛ 66,7% пациентов длительно наблюдались по поводу хронических заболеваний легких (хроническая обструктивная болезнь легких, хронический бронхит), а в 55,6% случаев (50 человек) находились на учете у врача - фтизиатра по поводу туберкулеза легких. По данным КТ ОГК в 66,7% случаев определялась диссеминация, в 48,9% - бронхоэктазии, в 46,7% - одиночные или множественные полости деструкции. В 72,2% случаев НТМБ были найдены в мокроте, в 33,3% - в БАС и в 22,2% обнаружены в операционном материале. В 14,4% случаев только оперативное вмешательство позволило установить диагноз микобактериоза.