The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis

The Dnmt2 enzyme utilizes the catalytic mechanism of eukaryotic DNA methyltransferases to methylate several tRNAs at cytosine 38. Dnmt2 mutant mice, flies, and plants were reported to be viable and fertile, and the biological function of Dnmt2 has remained elusive. Here, we show that endochondral ossification is delayed in newborn Dnmt2-deficient mice, which is accompanied by a reduction of the haematopoietic stem and progenitor cell population and a cell-autonomous defect in their differentiation. RNA bisulfite sequencing revealed that Dnmt2 methylates C38 of tRNA Asp(GTC), Gly(GCC), and Val(AAC), thus preventing tRNA fragmentation. Proteomic analyses from primary bone marrow cells uncovered systematic differences in protein expression that are due to specific codon mistranslation by tRNAs lacking Dnmt2-dependent methylation. Our observations demonstrate that Dnmt2 plays an important role in haematopoiesis and define a novel function of C38 tRNA methylation in the discrimination of near-cognate codons, thereby ensuring accurate polypeptide synthesis

Llama - Low Latency Adaptive Media Algorithm

In the recent years, HTTP Adaptive Bit Rate (ABR) streaming including Dynamic Adaptive Streaming over HTTP (DASH) has become the most popular technology for video streaming over the Internet. The client device requests segments of content using HTTP, with an ABR algorithm selecting the quality at which to request each segment to trade-off video quality with the avoidance of stalling. This introduces high latency compared to traditional broadcast methods, mostly in the client buffer which needs to hold enough data to absorb any changes in network conditions. Clients employ an ABR algorithm which monitors network conditions and adjusts the quality at which segments are requested to maximise the user's Quality of Experience. The size of the client buffer depends on the ABR algorithm's capability to respond to changes in network conditions in a timely manner, hence, low latency live streaming requires an ABR algorithm that can perform well with a small client buffer. In this paper, we present Llama - a new ABR algorithm specifically designed to operate in such scenarios. Our new ABR algorithm employs the novel idea of using two independent throughput measurements made over different timescales. We have evaluated Llama by comparing it against four popular ABR algorithms in terms of multiple QoE metrics, across multiple client settings, and in various network scenarios based on CDN logs of a commercial live TV service. Llama outperforms other ABR algorithms, improving the P.1203 Mean Opinion Score (MOS) as well as reducing rebuffering by 33% when using DASH, and 68% with CMAF in the lowest latency scenario

Research on the embryotoxic effect and carcinogenicity of the drug “BTF plus” – a means for normalizing metabolic processes in animals and poul-try

Laboratory studies were conducted to determine the embryotoxic effect and carcinogenicity of the veterinary drug “BTF plus” on white rats and white mice. The drug “BTF plus” is a complex vitamin-mineral drug based on butophosphane, L-carnitine, and cyanocobalamin, which is used to normalize and correct metabolic processes in animals and poultry. The drug is used for various types of animals and poultry as a stimulating, tonic and general strengthening agent for obstetric pathologies (complicated childbirth, postpartum complications, paresis, eclampsia, sexual cycle disorders); metabolic disorders caused by irrational feeding, malnutrition, asthenic syndrome, etc.; anemia with helminthiasis; secondary anemias, as an additional means in the treatment of magnesium and calcium deficiency; to increase muscle activity, with significant loads, overstrain and exhaustion in animals; to increase the body's resistance to various pathogens; to stimulate growth, development and live weight gain in young animals and poultry; as an additional means in the treatment of diseases caused by various factors (infectious and non-infectious origin). The drug “BTF plus”, under the conditions of subcutaneous administration to pregnant female rats in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not cause death and pathological changes in embryos do not have an embryotoxic and teratogenic effect since indicators of total, preimplantation, and postimplantation embryonic lethality in rats of the experimental groups had no significant differences compared to indicators in control and also did not show changes in the weight of the placenta, fetuses, and their cranio-caudal size. The drug “BTF plus”, under conditions of 5-day subcutaneous administration to white mice in doses (based on the absolute weight of the drug) of 200.0 and 2000.0 mg/kg of body weight, does not show a carcinogenic effect (during microscopic studies, the proportion of polychromatophilic erythrocytes was not probable deviations between themselves and was 0.117-0.133%, which is within the normal range of up to 0.2 %). Further studies will be the next stage of pre-registration tests aimed at studying the ecotoxicity of “BTF plus”, which is a mandatory material of the “Safety and residue studies” section of the dossier for this drug

Evaluation of CMAF in live streaming scenarios

HTTP Adaptive Streaming (HAS) technologies such as MPEG DASH are now used extensively to deliver television services to large numbers of viewers. In HAS, the client requests segments of content using HTTP, with an ABR algorithm selecting the quality at which to request each segment to trade-off video quality with the avoidance of stalling. This introduces significant end to end latency compared to traditional broadcast, due to the the client requiring a large enough buffer for the ABR algorithm to react to changes in network conditions in a timely manner. The recently standardised Common Media Application Format (CMAF) has helped address the issue of latency by defining segments as composed of independently transferable chunks. In this paper, we describe a simulation model we have developed to evaluate the performance of four popular ABR algorithms using DASH and CMAF in various low latency live streaming scenarios. Realistic network conditions are used for the evaluation, which are based on throughput data taken from the CDN logs of a commercial live TV service. We quantify the performance of the ABR algorithms using a selection of QoE metrics, and show that CMAF can significantly improve ABR performance in low delay scenarios

Joint profiling of DNA methylation and chromatin architecture in single cells.

We report a molecular assay, Methyl-HiC, that can simultaneously capture the chromosome conformation and DNA methylome in a cell. Methyl-HiC reveals coordinated DNA methylation status between distal genomic segments that are in spatial proximity in the nucleus, and delineates heterogeneity of both the chromatin architecture and DNA methylome in a mixed population. It enables simultaneous characterization of cell-type-specific chromatin organization and epigenome in complex tissues

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation

Objective: To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF). Methods: Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality, and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use, and competing events. Results: 2415 patients were included (mean age: 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex-adjusted hazard ratio (adjHR) of 0.99 (95% CI: 0.69-1.41) for subclinical hypothyroidism and 0.55 (95% CI: 0.23-1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR: 1.46, 95% CI: 1.04-2.05; adjHR: 1.70, 95% CI: 1.08-2.66, respectively, for the highest quintile vs the middle quintile). Results remained similar following multivariable adjustment and remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found. Conclusions: Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with a higher risk for HF

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance

Pharmaceuticals in sewage systems and surface waters – status quo

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Експериментальна оцінка гострої токсичності та подразнювальної дії “БТФ плюс” – ветеринарного лікарського засобу для нормалізації обмінних процесів у тварин і птиці

Laboratory studies were conducted to determine the acute toxicity of the veterinary drug “BTF plus” on white rats and white mice. The preparation “BTF plus” is a complex vitamin and mineral preparation, which is used to normalize and correct metabolic processes in poultry and animals. The drug is used for various types of animals and poultry as a stimulating, tonic and general strengthening agent for: obstetric pathologies (difficult births, postpartum complications, paresis, eclampsia, sexual cycle disorders); metabolic disorders caused by irrational feeding, malnutrition, asthenic syndrome, etc.; anemia with helminthiasis; secondary anemias, as an additional means in the treatment of magnesium and calcium deficiency; to increase muscle activity, with significant loads, overstrain and exhaustion in animals; to increase the body’s resistance to various pathogens; to stimulate growth, development and live weight gain in young animals; as an additional means in the treatment of diseases caused by various factors (infectious and non-infectious origin). Based on the results of determining the parameters of the acute toxicity of the drug “BTF plus” in the case of a single intragastric administration to white female rats, it was not possible to calculate the LD50, since the death of laboratory animals was not detected within 14 days after administration. At the same time, the maximum injected dose (based on the absolute weight of the drug) was 40000.0 mg/kg of body weight, which allows the drug to be classified as VI class of toxicity – the substances are relatively harmless (LD50 > 15000.0 mg/kg of body weight), and according to the degree of danger to IV class – low-hazardous substances (LD50 > 5000.0 mg/kg of body weight). Based on the results of determining the parameters of the acute toxicity of the drug “BTF plus” in the case of a single subcutaneous injection to white female rats and male mice, it was not possible to calculate the LD50, since the death of laboratory animals was not detected within 14 days after administration. At the same time, the maximum injected dose (based on the absolute weight of the drug) was 20000,0 and 40000.0 mg/kg of body weight for both species of animals, respectively, which allows it to be classified as VI class – relatively harmless substances (LD50Subcut > 4500 mg/kg of body weight). Further studies will be the next stage of pre-registration tests aimed at studying the embryotoxic effect of “BTF plus”, which is mandatory material of the “Safety and residue studies” section of the dossier for this drug.Проведені лабораторні дослідження з визначення гострої токсичності ветеринарного препарату “БТФ плюс” на білих щурах, білих мишах. Препарат “БТФ плюс” – комплексний вітамінно-мінеральний препарат, який застосовується для нормалізації та корекції обмінних процесів у птиці та тварин. Препарат застосовують різним видам тварин та птиці як стимулюючий, тонізуючий та загальнозміцнюючий засіб при: акушерських патологіях (складні пологи, післяпологові ускладнення, парези, еклампсії, порушення статевого циклу); порушеннях обміну речовин, що викликані нераціональною годівлею, недоїданням, астенічному синдромі тощо; анеміях при гельмінтозах; вторинних анеміях, як додатковий засіб при лікуванні дефіциту Магнію та Кальцію; для підвищення м’язової активності, при значних навантаженнях, перенапруженнях та виснаженні у тварин; для підвищення резистентності організму до дії різноманітних патогенів; для стимулювання росту, розвитку та приросту живої ваги у молодих тварин; як додатковий засіб при лікуванні захворювань, спричинених різними факторами (інфекційного та неінфекційного походження). За результатами визначення параметрів гострої токсичності препарату “БТФ плюс” – у разі одноразового внутрішньошлункового введення білим щурам-самкам LD50 розрахувати не вдалося, оскільки протягом 14 діб після введення загибелі лабораторних тварин не було виявлено. При цьому максимальна введена доза (за абсолютною масою препарату) становила 40000,0 мг/кг маси тіла, що дозволяє зарахувати препарат до VI класу токсичності – речовини порівняно нешкідливі (LD50 > 15000,0 мг/кг маси тіла), а за ступенем небезпечності до ІV класу – малонебезпечних речовин (LD50 > 5000,0 мг/кг маси тіла). За результатами визначення параметрів гострої токсичності препарату “БТФ плюс” – у разі одноразового підшкірного введення білим щурам-самкам і мишам-самцям LD50 розрахувати не вдалося, оскільки протягом 14 діб після введення загибелі лабораторних тварин не було виявлено. При цьому максимальна введена доза (за абсолютною масою препарату) становила 20000,0 і 40000,0 мг/кг маси тіла для обох видів тварин відповідно, що дозволяє зарахувати його до VІ класу – відносно нешкідливих речовин (LD50Subcut > 4500 мг/кг маси тіла). Подальші дослідження будуть черговим етапом передреєстраційних випробувань, спрямованих на вивчення ембріотоксичної дії “БТФ плюс”, що є обов’язковим матеріалом розділу “Дослідження щодо безпеки і залишків” досьє на даний лікарський засіб