Hydroxymethylated Cytosines Are Associated with Elevated C to G Transversion Rates

It has long been known that methylated cytosines deaminate at higher rates than unmodified cytosines and constitute mutational hotspots in mammalian genomes. The repertoire of naturally occurring cytosine modifications, however, extends beyond 5-methylcytosine to include its oxidation derivatives, notably 5-hydroxymethylcytosine. The effects of these modifications on sequence evolution are unknown. Here, we combine base-resolution maps of methyl- and hydroxymethylcytosine in human and mouse with population genomic, divergence and somatic mutation data to show that hydroxymethylated and methylated cytosines show distinct patterns of variation and evolution. Surprisingly, hydroxymethylated sites are consistently associated with elevated C to G transversion rates at the level of segregating polymorphisms, fixed substitutions, and somatic mutations in tumors. Controlling for multiple potential confounders, we find derived C to G SNPs to be 1.43-fold (1.22-fold) more common at hydroxymethylated sites compared to methylated sites in human (mouse). Increased C to G rates are evident across diverse functional and sequence contexts and, in cancer genomes, correlate with the expression of Tet enzymes and specific components of the mismatch repair pathway (MSH2, MSH6, and MBD4). Based on these and other observations we suggest that hydroxymethylation is associated with a distinct mutational burden and that the mismatch repair pathway is implicated in causing elevated transversion rates at hydroxymethylated cytosines

Neutrino-Nucleus Reactions and Muon Capture in 12C

The neutrino-nucleus cross section and the muon capture rate are discussed within a simple formalism which facilitates the nuclear structure calculations. The corresponding formulae only depend on four types of nuclear matrix elements, which are currently used in the nuclear beta decay. We have also considered the non-locality effects arising from the velocity-dependent terms in the hadronic current. We show that for both observables in 12C the higher order relativistic corrections are of the order of ~5 only, and therefore do not play a significant role. As nuclear model framework we use the projected QRPA (PQRPA) and show that the number projection plays a crucial role in removing the degeneracy between the proton-neutron two quasiparticle states at the level of the mean field. Comparison is done with both the experimental data and the previous shell model calculations. Possible consequences of the present study on the determination of the $\nu_\mu ->\nu_e$ neutrino oscillation probability are briefly addressed.Comment: 29 pages, 6 figures, Revtex4. Several changes were made to the previous manuscript, the results and final conclusions remain unalterable. It has been accepted for publication as a Regular Article in Physical Review

Proton and alpha radiation-induced mutational profiles in human cells

Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.© 2023. The Author(s)

Precise Measurement of the Pi+ -> Pi0 e+ nu Branching Ratio

Using a large acceptance calorimeter and a stopped pion beam we have made a precise measurement of the rare Pi+ -> Pi0 e+ Nu,(pi_beta) decay branching ratio. We have evaluated the branching ratio by normalizing the number of observed pi_beta decays to the number of observed Pi+ -> e+ Nu, (pi_{e2}) decays. We find the value of Gamma(Pi+ -> Pi0 e+ Nu)/Gamma(total) = [1.036 +/- 0.004(stat.) +/- 0.004(syst.) +/- 0.003(pi_{e2})] x 10^{-8}$, where the first uncertainty is statistical, the second systematic, and the third is the pi_{e2} branching ratio uncertainty. Our result agrees well with the Standard Model prediction.Comment: 4 pages, 5 figures, 1 table, revtex4; changed content; updated analysi

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio

Measurement of Inverse Pion Photoproduction at Energies Spanning the N(1440) Resonance

Differential cross sections for the process pi^- p -> gamma n have been measured at Brookhaven National Laboratory's Alternating Gradient Synchrotron with the Crystal Ball multiphoton spectrometer. Measurements were made at 18 pion momenta from 238 to 748 MeV/c, corresponding to E_gamma for the inverse reaction from 285 to 769 MeV. The data have been used to evaluate the gamma n multipoles in the vicinity of the N(1440) resonance. We compare our data and multipoles to previous determinations. A new three-parameter SAID fit yields 36 +/- 7 (GeV)^-1/2 X 10^-3 for the A^n_1/2 amplitude of the P_11.Comment: 14 pages, 8 figures, submitted to PR

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas