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

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

Effect of cadmium on cytosine hydroxymethylation in gastropod hepatopancreas

5-Hydroxymethylcytosine (5hmC) is an important, yet poorly understood epigenetic DNA modification, especially in invertebrates. Aberrant genome-wide 5hmC levels have been associated with cadmium (Cd) exposure in humans, but such information is lacking for invertebrate bioindicators. Here, we aimed to determine whether this epigenetic mark is present in DNA of the hepatopancreas of the land snail Cantareus aspersus and is responsive to Cd exposure. Adult snails were reared under laboratory conditions and exposed to graded amounts of dietary cadmium for 14 days. Weight gain was used as a sublethal endpoint, whereas survival as a lethal endpoint. Our results are the first to provide evidence for the presence of 5hmC in DNA of terrestrial mollusks; 5hmC levels are generally low with the measured values falling below 0.03%. This is also the first study to investigate the interplay of Cd with DNA hydroxymethylation levels in a non-human animal study system. Cadmium retention in the hepatopancreas of C. aspersus increased from a dietary Cd dose of 1 milligram per kilogram dry weight (mg/kg d. wt). For the same treatment, we identified the only significant elevation in percentage of samples with detectable 5hmC levels despite the lack of significant mortalities and changes in weight gain among treatment groups. These findings indicate that 5hmC is an epigenetic mark that may be responsive to Cd exposure, thereby opening a new aspect to invertebrate environmental epigenetics

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

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

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

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

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

Pharmaceuticals in sewage systems and surface waters – status quo

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