Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro.

A role for choline during early stages of mammalian embryogenesis has not been established, although recent studies show that inhibitors of choline uptake and metabolism, 2-dimethylaminoethanol (DMAE), and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), produce neural tube defects in mouse embryos grown in vitro. To determine potential mechanisms responsible for these abnormalities, choline metabolism in the presence or absence of these inhibitors was evaluated in cultured, neurulating mouse embryos by using chromatographic techniques. Results showed that 90%-95% of 14C-choline was incorporated into phosphocholine and phosphatidylcholine (PtdCho), which was metabolized to sphingomyelin. Choline was oxidized to betaine, and betaine homocysteine methyltransferase was expressed. Acetylcholine was synthesized in yolk sacs, but 70 kDa choline acetyltransferase was undetectable by immunoblot. DMAE reduced embryonic choline uptake and inhibited phosphocholine, PtdCho, phosphatidylethanolamine (PtdEtn), and sphingomyelin synthesis. ET-18-OCH3 also inhibited PtdCho synthesis. In embryos and yolk sacs incubated with 3H-ethanolamine, 95% of recovered label was PtdEtn, but PtdEtn was not converted to PtdCho, which suggested that phosphatidylethanolamine methyltransferase (PeMT) activity was absent. In ET-18-OCH3 treated yolk sacs, PtdEtn was increased, but PtdCho was still not generated through PeMT. Results suggest that endogenous PtdCho synthesis is important during neurulation and that perturbed choline metabolism contributes to neural tube defects produced by DMAE and ET-18-OCH3

Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency.

Hyperhomocysteinemia, a proposed risk factor for cardiovascular disease, is also observed in other common disorders. The most frequent genetic cause of hyperhomocysteinemia is a mutated methylenetetrahydrofolate reductase (MTHFR), predominantly when folate status is impaired. MTHFR synthesizes a major methyl donor for homocysteine remethylation to methionine. We administered the alternate choline-derived methyl donor, betaine, to wild-type mice and to littermates with mild or severe hyperhomocysteinemia due to hetero- or homozygosity for a disruption of the Mthfr gene. On control diets, plasma homocysteine and liver choline metabolite levels were strongly dependent on the Mthfr genotype. Betaine supplementation decreased homocysteine in all three genotypes, restored liver betaine and phosphocholine pools, and prevented severe steatosis in Mthfr-deficient mice. Increasing betaine intake did not further decrease homocysteine. In humans with cardiovascular disease, we found a significant negative correlation between plasma betaine and homocysteine concentrations. Our results emphasize the strong interrelationship between homocysteine, folate, and choline metabolism. Hyperhomocysteinemic Mthfr-compromised mice appear to be much more sensitive to changes of choline/betaine intake than do wild-type animals. Hyperhomocysteinemia, in the range of that associated with folate deficiency or with homozygosity for the 677T MTHFR variant, may be associated with disturbed choline metabolism

Phylogenomic analysis of a 55.1 kb 19-gene dataset resolves a monophyletic Fusarium that includes the Fusarium solani Species Complex

Scientific communication is facilitated by a data-driven, scientifically sound taxonomy that considers the end-user¿s needs and established successful practice. In 2013, the Fusarium community voiced near unanimous support for a concept of Fusarium that represented a clade comprising all agriculturally and clinically important Fusarium species, including the F. solani species complex (FSSC). Subsequently, this concept was challenged in 2015 by one research group who proposed dividing the genus Fusarium into seven genera, including the FSSC described as members of the genus Neocosmospora, with subsequent justification in 2018 based on claims that the 2013 concept of Fusarium is polyphyletic. Here, we test this claim and provide a phylogeny based on exonic nucleotide sequences of 19 orthologous protein-coding genes that strongly support the monophyly of Fusarium including the FSSC. We reassert the practical and scientific argument in support of a genus Fusarium that includes the FSSC and several other basal lineages, consistent with the longstanding use of this name among plant pathologists, medical mycologists, quarantine officials, regulatory agencies, students, and researchers with a stake in its taxonomy. In recognition of this monophyly, 40 species described as genus Neocosmospora were recombined in genus Fusarium, and nine others were renamed Fusarium. Here the global Fusarium community voices strong support for the inclusion of the FSSC in Fusarium, as it remains the best scientific, nomenclatural, and practical taxonomic option availabl

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Centrality dependence of inclusive J/\u3c8 production in p-Pb collisions at 1asNN = 5.02 TeV

We present a measurement of inclusive J/\u3c8 production in p-Pb collisions at 1asNN = 5.02TeV as a function of the centrality of the collision, as estimated from the energy deposited in the Zero Degree Calorimeters. The measurement is performed with the ALICE detector down to zero transverse momentum, pT, in the backward ( 124.46 < ycms < 122.96) and forward (2.03 < ycms < 3.53) rapidity intervals in the dimuon decay channel and in the mid-rapidity region ( 121.37 < ycms < 0.43) in the dielectron decay channel. The backward and forward rapidity intervals correspond to the Pb-going and p-going direction, respectively. The pT-differential J/\u3c8 production cross section at backward and forward rapidity is measured for several centrality classes, together with the corresponding average pT and pT2 values. The nuclear modification factor is presented as a function of centrality for the three rapidity intervals, and as a function of pT for several centrality classes at backward and forward rapidity. At mid- and forward rapidity, the J/\u3c8 yield is suppressed up to 40% compared to that in pp interactions scaled by the number of binary collisions. The degree of suppression increases towards central p-Pb collisions at forward rapidity, and with decreasing pT of the J/\u3c8. At backward rapidity, the nuclear modification factor is compatible with unity within the total uncertainties, with an increasing trend from peripheral to central p-Pb collisions

Centrality dependence of high-pT D meson suppression in Pb-Pb collisions at 1asNN = 2.76 TeV

The nuclear modification factor, RAA, of the prompt charmed mesons D0, D+ and D 17+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at a centre-of-mass energy 1asNN = 2.76 TeV in two transverse momentum intervals, 5 < pT < 8GeV/c and 8 < pT < 16GeV/c, and in six collision centrality classes. The RAA shows a maximum suppression of a factor of 5\u20136 in the 10% most central collisions. The suppression and its centrality dependence are compatible within uncertainties with those of charged pions. A comparison with the RAA of non-prompt J/\u3c8 from B meson decays, measured by the CMS Collaboration, hints at a larger suppression of D mesons in the most central collisions

Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia

Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis–remission–relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance

Välttelevän kiintymyssuhteen merkitys lapsen hyvinvoinnille

Tarkoituksena tässä opinnäytetyössä on koota tutkimustietoa välttelevästä kiintymyssuhteesta ja sen merkityksestä lapsen hyvinvoinnille. Tavoitteena oli kehittää ammatillista osaamista teoriapohjan osalta ja käsitellä tutkittavaa aihetta psykiatrisen hoitotyön näkökulmasta, mikä on suuntautumiseni. Tutkimuskysymys on jaettu kahteen osaan: vanhempien ja lapsen välinen kiintymyssuhde ja lapsen kehitys ja hyvinvointi. Näiden osien ulottuvilta on haettu tutkimusartikkeleita, tutkimusraportteja ja asiantuntijakirjoituksia, joista on koottu tiivistelmiä kirjallisuuskatsauksen tapaan. Pohdinnassa on eritelty aineistoa tarkemmin tutkimuskysymyksen osalta. Kiintymyssuhde kehittyy lapsella varhaisen vuorovaikutuksen kautta 0–2-vuotiaana. Jos vanhemmat laiminlyövät kommunikoinnin lapsen kanssa, emotionaalinen kehitys jää vajaaksi eikä lapsi opi ilmaisemaan omia tarpeitaan ja tunteitaan. Välttelevän kiintymyssuhteen seuraukset voivat olla laajat epäsosiaalisuudesta kognitiivisiin häiriöihin. Epäsosiaalisuuteen kytkeytyviin häiriöihin kuuluu puhumattomuus, eristäytyminen ja laajemmin kroonistunut masennus, mihin taas liittyy vahva itsetuhoisuuden riski