The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence.

YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development

A Review on Antitumor and Antiviral Potential of Cranberries (Vaccinium Vitis-Idaea) Origin from Bulgaria

A major goal in antitumor and antiviral therapy is to find active ingredients that selectively suppress the proliferation of tumor cells or inhibit viral replication and proliferation. In this connection, the antitumor and antiviral activity of natural products with proven phytochemical properties and pharmacological significance are actively investigated. A promising candidate are Bulgarian cranberries from high mountain plant populations, which are a valuable natural source of food and have proven healing properties in urinary tract infections, eye diseases and cardiovascular disorders, as well as prevention of hypertension and diabetes. The active components of Vaccinium vitis-idaea L. are polyphenols and anthocyanins which belong to classes of plant components with high antioxidant, antimicrobial, cytotoxic and antiproliferative activity. Cranberries contain a high percentage and variety of vitamins (A,  E, C,  etc.) and a number of minerals (K, Ca, Mg, P, Na). In the world regions where endemic measles outbreaks occur, for secondary prevention and avoidance of complications including blindness, WHO recommends the use of high doses of vitamin A in children under 5 years of age. Bulgarian cranberries are a valuable source of vitamins A and C.The assessement of biological activity of the individual components and fractions in the composition of the Bulgarian cranberries may help to identify substances with antitumor and/or antiviral activity that could potentially be useful in future development of new therapeutic agents

NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Summary: Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3′ untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

<p>Abstract</p> <p>Background</p> <p>The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in <it>in vivo </it>experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their <it>in vitro </it>complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).</p> <p>Results</p> <p>New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)₂(H₂O)₂] (<b>1</b>) and [Pb(Sal)(NO₃)] (<b>2</b>), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield <b>1</b>. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex <b>2 </b>consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.</p> <p>Conclusion</p> <p>The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.</p

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance

Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

International audienc

Eye lens dose assessment in interventional cardiology

Въведение. Медицинските специалисти, провеждащи интервенционални процедури под рентгенов контрол в интервенционалната кардиология, са изложени на риск от лъчевоиндуцирана катаракта при надвишаване на годишната граница на дозата на очната леща от 20 mSv. Цел: Целта на проучването е да се направи оценка на дозата на очната леща на медицински специалисти, работещи в три отделения по интервенционална кардиология, да се анализира зависимостта между лъчевото натоварване на пациента и дозата на очната леща на основния оператор, и да се изследва ефективността на защитните очила без странични оловни защити. Материал и методи: Измерванията се проведоха в три отделения по инвазивна кардиология, като в изследванията се включиха четирима лекари и шест медицински сестри. Дозата на очната леща бе измервана с пасивни дозиметри за очна леща EYE-DTM (Radcard). Резултати: Годишната доза на очната леща за медицинските сестри варира от 1,6 mSv до 4,3 mSv. Оценената доза на очната леща за основния оператор е от 3,2 mSv до 31,4 mSv. Отслабването на изследваните защитни очила без странична защита е с фактор от 1 до 1,1. Изводи: Резулатите показват, че съществува риск за превишаване на годишната граница на дозата на очната леща от 20 mSv. Дозата на очната леща зависи от работното натоварване и клиничната сложност на провежданите процедури. Дозата на очната леща за медицинските сестри е няколко пъти по-ниска от граничната, което се обяснява с по-голямото разстояние от пациента и частичното екраниране от основния оператор. Защитните очила без странична защита не осигуряват необходимата защита на очната леща, в случай на странично облъчване. Introduction: Medical professionals performing fluoroscopy guided interventional procedures in cardiology are exposed to a risk of radiation induced cataract, especially if the eye lens dose exceeds the annual dose limit of 20 mSv. Aim: The aim of the current study is to measure the eye lens exposure in three interventional cardiology departments, to analyze the relationship between patient dose and eye lens dose and to study the effectiveness of lead goggles without side protection. Material and methods: Measurements were performed in three departments with participation of 4 interventional cardiologists and 6 nurses. The exposure of the eye lens was measured with EYE-DTM (Radcard) passive dosimeters. Results: For nurses the annual eye lens dose varied from 1.6 mSv to 4.3 mSv. For the interventional cardiologists the results were between 3.2 mSv and 31.4 mSv. The dose reduction factor of the studied safety goggles without side protection is 1 and 1.1. Conclusions: There is a risk of exceeding the annual exposure limit of 20 mSv among interventional cardiologists The eye lens exposure depends on the workload and the clinical complexity of the procedures, as well as on the use of radiation protection devices. Due to the specifics of the procedures, the use of goggles with side protection is recommended. The eye lens dose for nurses is lower than the annual limit, which can be explained with the larger distance between the patient and the nurses and partial shielding by the main operator. Lead glasses without side shielding are not recommended because the exposure occurs from the side

Phytochemical Composition, Anti-Inflammatory and ER Stress-Reducing Potential of Sambucus ebulus L. Fruit Extract

Sambucus ebulus L. (SE) fruits are used for their immunostimulation, hematopoietic and antiviral potential. Recently, we focused on analyzing the mechanism underlying SE fruit aqueous extract’s (FAE) immunomodulation and anti-inflammatory activities, with attention to its endoplasmic reticulum (ER) stress-reducing potential. J774A.1 macrophages were treated with SE FAE alone or in conditions of lipopolysaccharides (LPS) stimulation. Using GC–MS and LC–MS/MS, its phytochemical composition was analyzed. To measure transcription and protein levels, we used qPCR and Western blot, respectively. The prevailing phytochemicals in SE FAE were hydroxycinnamic acids, proanthocyanidins and anthocyanins. The content of some amino acids, organic acids, alcohols, fatty acids and esters were newly reported. Extracts exerted an immunostimulation potential by stimulating IL-6, TNFα, Ccl2, COX2 and iNOS transcription, without inducing ER stress. SE FAE suppressed the LPS-induced transcription of inflammation related genes (IL-1β, IL-6, TNFα, Ccl2, Icam-1, Fabp4, COX2, iNOS, Noxo1, IL-1ra, Sirt-1) and reduced the protein levels of iNOS, peIF2α, ATF6α and CHOP. The effects were comparable to that of salicylic acid. SE suppresses LPS-stimulated inflammatory markers on the transcription and translation levels. Targeting ER stress is possibly another mechanism underlying its anti-inflammatory potential. These findings reveal the potential of SE fruits as a beneficial therapeutic of inflammation and ER stress-related pathological conditions