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DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here, we demonstrate that Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that the de novo methylation activity of Dnmt1 depends on Uhrf1, and its genomic recruitment overlaps with regions that enrich for Uhrf1, Trim28 and H3K9 trimethylation. Our data demonstrate that Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development. The canonical DNA methylation maintenance enzyme Dnmt1 displays global de novo methylation activity with greater targeting towards IAP transposons, which may contribute to their stable repression during early development.

Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.

Background CrMYC2 is an early jasmonate-responsive bHLH transcription factor involved in the regulation of the expression of the genes of the terpenic indole alkaloid biosynthesis pathway in Catharanthus roseus . In this paper, we identified the amino acid domains necessary for the nuclear targeting of CrMYC2. Findings We examined the intracellular localization of whole CrMYC2 and of various deletion mutants, all fused with GFP, using a transient expression assay in onion epidermal cells. Sequence analysis of this protein revealed the presence of four putative basic nuclear localization signals (NLS). Assays showed that none of the predicted NLS is active alone. Further functional dissection of CrMYC2 showed that the nuclear targeting of this transcription factor involves the cooperation of three domains located in the C-terminal region of the protein. The first two domains are located at amino acid residues 454-510 and 510-562 and contain basic classical monopartite NLSs; these regions are referred to as NLS3 (KRPRKR) and NLS4 (EAERQRREK), respectively. The third domain, between residues 617 and 652, is rich in basic amino acids that are well conserved in other phylogenetically related bHLH transcription factors. Our data revealed that these three domains are inactive when isolated but act cooperatively to target CrMYC2 to the nucleus. Conclusions This study identified three amino acid domains that act in cooperation to target the CrMYC2 transcription factor to the nucleus. Further fine structure/function analysis of these amino acid domains will allow the identification of new NLS domains and will allow the investigation of the related molecular mechanisms involved in the nuclear targeting of the CrMYC2 bHLH transcription factor.

Water balance in the lung is controlled via active Na+and Cl-transport. Electrophysiological measurements on lung epithelial cells demonstrated the presence of a Na+channel that is inhibited by amiloride (K0.5= 90 nM) and some of its derivatives such as phenamil (K0.5= 19 nM) and benzamil (K0.5= 14 nM) but not by ethylisopropylamiloride. An amiloride-sensitive Na+channel of 4 pS was recorded from outside-out patches excised from the apical membrane. This channel is highly selective for Na+(PNa +/PK+≥ 10). Isolation of a human lung cDNA led to the primary structure of the lung Na+channel. The corresponding protein is 669 residues long and has two large hydrophobic domains. An amiloride-sensitive Na+-selective current apparently identical to the one observed in lung epithelial cells was recorded after expression of the cloned channel in oocytes. The level of the mRNA for the Na+channel was highly increased from fetal to newborn and adult stages. This observation indicates that the increased Na+reabsorption that occurs at birth as a necessary event to pass to an air-breathing environment is probably associated with control of transcription of this Na+channel. The human gene for the lung Na+channel was mapped on chromosome 12p13.

This document presents the opinion of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), established from the work of its Working Group on “Risks associated with the consumption of Nitrites and Nitrates\" (NiNa WG) and validated by its Expert Committees on “Assessment of the biological risks in foods” (CES BIORISK) and “Assessment of physico‐chemical risks in food” (CES ERCA). Following a request from the Directorate General for Health, the Directorate General for Food and the Directorate General for Competition, Consumer Affairs and Fraud Control, ANSES was asked to deliver an opinion on the risks linked to nitrites and nitrates. Specifically, ANSES provided a scientific assessment associated with the following work themes regarding questions of (i) the impact of reducing nitrite/nitrate levels in foodstuffs on the fate of pathogenic bacteria in certain foods, (ii) the assessment of overall exposure to nitrates and nitrites from all sources in France and the proposal of actions that could help reduce this exposure, (iii) evaluating if new scientific knowledge could justify revisiting EFSA's ADIs/Health‐Based Guidance Values (HBGVs) for nitrates and nitrites, and (iv) better characterizing their link to human cancer risk from meat product consumption. The opinion first presents the substances of interest, their origin and the regulatory framework. Then this opinion sets out the conclusions of the microbiological risk for three foodborne pathogens associated with reducing nitrate/nitrite levels as additives in three types of cured meats. This is followed by a presentation of the conclusions relating to the assessment of the available epidemiological and toxicological data in the light of recent scientific data. Finally, this enables the characterization of the risk associated with ingested nitrates and nitrites after exposure has been estimated. The opinion provides recommendations to continue epidemiological studies to confirm or refute suspected relationships for certain cancers and to conduct experimental studies for the establishment of ADIs considering the combined exposure to nitrates, nitrites and nitroso compounds. Furthermore, reducing the population's exposure to nitrites and nitrates involves collective and individual measures. As part of collective measures, in addition to controlling the quality of water intended for human consumption, a relevant measure would be to reduce the use of nitrites in processed meat products while implementing strict compensatory measures to address microbiological risk. This opinion finally emphasizes the importance of individual measures, by adhering to recommendations for processed meat consumption, limiting it to 150g/week, and diversifying the consumption of fruits and vegetables.

The study of propagation of Ultra High Energy Cosmic Rays (UHECR) is a key step in order to unveil the secret of their origin. Up to now it was considered only the influence of the galactic and the extragalactic magnetic fields. In this article we focus our analysis on the influence of the magnetic field of the galaxies standing between possible UHECR sources and us. Our main approach is to start from the well known galaxy distribution up to 120 Mpc. We use the most complete galaxy catalog: the LEDA catalog. Inside a sphere of 120 Mpc around us, we extract 60130 galaxies with known position. In our simulations we assign a Halo Dipole magnetic Field (HDF) to each galaxy. The code developed is able to retro-propagate a charged particle from the arrival points of UHECR data across our galaxies sample. We present simulations in case of Virgo cluster and show that there is a non negligible deviation in the case of protons of \\(7 \\times 10^{19}\\) eV, even if the \\(B\\) value is conservative. Then special attention is devoted to the AGASA triplet where we find that NGC3998 and NGC3992 could be possible candidates as sources.

We propose a model of interdependent scheduling games in which each player controls a set of services that they schedule independently. A player is free to schedule his own services at any time; however, each of these services only begins to accrue reward for the player when all predecessor services, which may or may not be controlled by the same player, have been activated. This model, where players have interdependent services, is motivated by the problems faced in planning and coordinating large-scale infrastructures, e.g., restoring electricity and gas to residents after a natural disaster or providing medical care in a crisis when different agencies are responsible for the delivery of staff, equipment, and medicine. We undertake a game-theoretic analysis of this setting and in particular consider the issues of welfare maximization, computing best responses, Nash dynamics, and existence and computation of Nash equilibria.

The aim of this study is to evaluate if the sweat produced by COVID-19 persons (SARS-CoV-2 PCR positive) has a different odour for trained detection dogs than the sweat produced by non COVID-19 persons. The study was conducted on 3 sites, following the same protocol procedures, and involved a total of 18 dogs. A total of 198 armpits sweat samples were obtained from different hospitals. For each involved dog, the acquisition of the specific odour of COVID-19 sweat samples required from one to four hours, with an amount of positive samples sniffing ranging from four to ten. For this proof of concept, we kept 8 dogs of the initial group (explosive detection dogs and colon cancer detection dogs), who performed a total of 368 trials, and will include the other dogs in our future studies as their adaptation to samples scenting takes more time. The percentages of success of the dogs to find the positive sample in a line containing several other negative samples or mocks (2 to 6) were 100p100 for 4 dogs, and respectively 83p100, 84p100, 90p100 and 94p100 for the others, all significantly different from the percentage of success that would be obtained by chance alone. We conclude that there is a very high evidence that the armpits sweat odour of COVID-19+ persons is different, and that dogs can detect a person infected by the SARS-CoV-2 virus. Competing Interest Statement The authors have declared no competing interest.