Loss of DNMT1o Disrupts Imprinted X Chromosome Inactivation and Accentuates Placental Defects in Females

The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat-/- mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation. © 2013 McGraw et al

Characterization of Granulations of Calcium and Apatite in Serum as Pleomorphic Mineralo-Protein Complexes and as Precursors of Putative Nanobacteria

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Observation of B→D(∗)K−KS0{B\to D^{(*)} K^- K^{0}_S} decays using the 2019-2022 Belle II data sample

We present a measurement of the branching fractions of four $B^{0,-}\to D^{(*)+,0} K^- K^{0}_S$ decay modes. The measurement is based on data from SuperKEKB electron-positron collisions at the $\Upsilon(4S)$ resonance collected with the Belle II detector and corresponding to an integrated luminosity of ${362~\text{fb}^{-1}}$. The event yields are extracted from fits to the distributions of the difference between expected and observed $B$ meson energy to separate signal and background, and are efficiency-corrected as a function of the invariant mass of the $K^-K_S^0$ system. We find the branching fractions to be: $$\text{B}(B^-\to D^0K^-K_S^0)=(1.89\pm 0.16\pm 0.10)\times 10^{-4},$$ $$\text{B}(\overline B{}^0\to D^+K^-K_S^0)=(0.85\pm 0.11\pm 0.05)\times 10^{-4},$$ $$\text{B}(B^-\to D^{*0}K^-K_S^0)=(1.57\pm 0.27\pm 0.12)\times 10^{-4},$$ $$\text{B}(\overline B{}^0\to D^{*+}K^-K_S^0)=(0.96\pm 0.18\pm 0.06)\times 10^{-4},$$ where the first uncertainty is statistical and the second systematic. These results include the first observation of $\overline B{}^0\to D^+K^-K_S^0$, $B^-\to D^{*0}K^-K_S^0$, and $\overline B{}^0\to D^{*+}K^-K_S^0$ decays and a significant improvement in the precision of $\text{B}(B^-\to D^0K^-K_S^0)$ compared to previous measurements

Angular analysis of B+→ρ+ρ0B^+ \to \rho^+\rho^0 decays reconstructed in 2019, 2020, and 2021 Belle II data

We report on a Belle II measurement of the branching fraction ($\mathcal{B}$), longitudinal polarization fraction ($f_L$), and CP asymmetry ($\mathcal{A}_{CP}$) of $B^+\to \rho^+\rho^0$ decays. We reconstruct $B^+\to \rho^+(\to \pi^+\pi^0(\to \gamma\gamma))\rho^0(\to \pi^+\pi^-)$ decays in a sample of SuperKEKB electron-positron collisions collected by the Belle II experiment in 2019, 2020, and 2021 at the $\Upsilon$(4S) resonance and corresponding to 190 fb$^{-1}$ of integrated luminosity. We fit the distributions of the difference between expected and observed $B$ candidate energy, continuum-suppression discriminant, dipion masses, and decay angles of the selected samples, to determine a signal yield of $345 \pm 31$ events. The signal yields are corrected for efficiencies determined from simulation and control data samples to obtain $\mathcal{B}(B^+ \to \rho^+\rho^0) = [23.2^{+\ 2.2}_{-\ 2.1} (\rm stat) \pm 2.7 (\rm syst)]\times 10^{-6}$,$f_L = 0.943 ^{+\ 0.035}_{-\ 0.033} (\rm stat)\pm 0.027(\rm syst)$, and$\mathcal{A}_{CP}=-0.069 \pm 0.068(\rm stat) \pm 0.060 (\rm syst)$. The results agree with previous measurements. This is the first measurement of$\mathcal{A}_{CP}$in$B^+\to \rho^+\rho^0$ decays reported by Belle II

Determination of ∣Vub∣|V_{ub}| from untagged B0→π−ℓ+νℓB^0\to\pi^- \ell^+ \nu_{\ell} decays using 2019-2021 Belle II data

We present an analysis of the charmless semileptonic decay $B^0\to\pi^- \ell^+ \nu_{\ell}$, where $\ell = e, \mu$, from 198.0 million pairs of $B\bar{B}$ mesons recorded by the Belle II detector at the SuperKEKB electron-positron collider. The decay is reconstructed without identifying the partner $B$ meson. The partial branching fractions are measured independently for $B^0\to\pi^- e^+ \nu_{e}$ and $B^0\to\pi^- \mu^+ \nu_{\mu}$ as functions of $q^{2}$ (momentum transfer squared), using 3896 $B^0\to\pi^- e^+ \nu_{e}$ and 5466 $B^0\to\pi^- \mu^+ \nu_{\mu}$ decays. The total branching fraction is found to be $(1.426 \pm 0.056 \pm 0.125) \times 10^{-4}$ for $B^0\to\pi^- \ell^+ \nu_{\ell}$ decays, where the uncertainties are statistical and systematic, respectively. By fitting the measured partial branching fractions as functions of $q^{2}$, together with constraints on the nonperturbative hadronic contribution from lattice QCD calculations, the magnitude of the Cabibbo-Kobayashi-Maskawa matrix element $V_{ub}$, $(3.55 \pm 0.12 \pm 0.13 \pm 0.17) \times 10^{-3}$, is extracted. Here, the first uncertainty is statistical, the second is systematic and the third is theoretical

Reconstruction of B→ρℓνℓB \to \rho \ell \nu_\ell decays identified using hadronic decays of the recoil BB meson in 2019 -- 2021 Belle II data

We present results on the semileptonic decays $B^0 \to \rho^- \ell^+ \nu_\ell$ and $B^+ \to \rho^0 \ell^+ \nu_\ell$ in a sample corresponding to 189.9/fb of Belle II data at the SuperKEKB $e^- e^+$ collider. Signal decays are identified using full reconstruction of the recoil $B$ meson in hadronic final states. We determine the total branching fractions via fits to the distributions of the square of the "missing" mass in the event and the dipion mass in the signal candidate and find ${\mathcal{B}(B^0\to\rho^-\ell^+ \nu_\ell) = (4.12 \pm 0.64(\mathrm{stat}) \pm 1.16(\mathrm{syst})) \times 10^{-4}}$ and ${\mathcal{B}({B^+\to\rho^0\ell^+\nu_\ell}) = (1.77 \pm 0.23 (\mathrm{stat}) \pm 0.36 (\mathrm{syst})) \times 10^{-4}}$ where the dominant systematic uncertainty comes from modeling the nonresonant $B\to (\pi\pi)\ell^+\nu_\ell$ contribution

Measurement of the branching fractions and CPCP asymmetries of B+→π+π0B^+ \rightarrow \pi^+ \pi^0 and B+→K+π0B^+ \rightarrow K^+ \pi^0 decays in 2019-2021 Belle II data

We determine the branching fractions ${\mathcal{B}}$ and $CP$ asymmetries ${\mathcal{A}_{{\it CP}}}$ of the decays $B^+ \rightarrow \pi^+ \pi^0$ and $B^+ \rightarrow K^+ \pi^0$. The results are based on a data set containing 198 million bottom-antibottom meson pairs corresponding to an integrated luminosity of $190\;\text{fb}^{-1}$ recorded by the Belle II detector in energy-asymmetric electron-positron collisions at the $\Upsilon (4S)$ resonance. We measure ${\mathcal{B}(B^+ \rightarrow \pi^+ \pi^0) = (6.12 \pm 0.53 \pm 0.53)\times 10^{-6}}$, ${\mathcal{B}(B^+ \rightarrow K^+ \pi^0) = (14.30 \pm 0.69 \pm 0.79)\times 10^{-6}}$, ${\mathcal{A}_{{\it CP}}(B^+ \rightarrow \pi^+ \pi^0) = -0.085 \pm 0.085 \pm 0.019}$, and ${\mathcal{A}_{{\it CP}}(B^+ \rightarrow K^+ \pi^0) = 0.014 \pm 0.047 \pm 0.010}$, where the first uncertainties are statistical and the second are systematic. These results improve a previous Belle II measurement and agree with the world averages