Inferring and perturbing cell fate regulomes in human brain organoids

Self-organizing neural organoids grown from pluripotent stem cells(1-3) combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development. Here we acquire single-cell transcriptome and accessible chromatin data over a dense time course in human organoids covering neuroepithelial formation, patterning, brain regionalization and neurogenesis, and identify temporally dynamic and brain-region-specific regulatory regions. We developed Pando-a flexible framework that incorporates multi-omic data and predictions of transcription-factor-binding sites to infer a global gene regulatory network describing organoid development. We use pooled genetic perturbation with single-cell transcriptome readout to assess transcription factor requirement for cell fate and state regulation in organoids. We find that certain factors regulate the abundance of cell fates, whereas other factors affect neuronal cell states after differentiation. We show that the transcription factor GLI3 is required for cortical fate establishment in humans, recapitulating previous research performed in mammalian model systems. We measure transcriptome and chromatin accessibility in normal or GLI3-perturbed cells and identify two distinct GLI3 regulomes that are central to telencephalic fate decisions: one regulating dorsoventral patterning with HES4/5 as direct GLI3 targets, and one controlling ganglionic eminence diversification later in development. Together, we provide a framework for how human model systems and single-cell technologies can be leveraged to reconstruct human developmental biology

Measurements of the masses and widths of the Σc(2455)0/++\Sigma_{c}(2455)^{0/++} and Σc(2520)0/++\Sigma_{c}(2520)^{0/++} baryons

We present measurements of the masses and decay widths of the baryonic states $\Sigma_{c}(2455)^{0/++}$ and $\Sigma_{c}(2520)^{0/++}$ using a data sample corresponding to an integrated luminosity of 711 fb$^{-1}$ collected with the Belle detector at the KEKB $e^{+}e^{-}$ asymmetric-energy collider operating at the $\Upsilon(4S)$ resonance. We report the mass differences with respect to the $\Lambda_{c}^{+}$ baryon $M(\Sigma_{c}(2455)^{0})-M(\Lambda_{c}^{+}) = 167.29\pm0.01\pm0.02$ MeV/$c^{2}$, $M(\Sigma_{c}(2455)^{++})-M(\Lambda_{c}^{+}) = 167.51\pm0.01\pm0.02$ MeV/$c^{2}$, $M(\Sigma_{c}(2520)^{0})-M(\Lambda_{c}^{+}) = 231.98\pm0.11\pm0.04$ MeV/$c^{2}$, $M(\Sigma_{c}(2520)^{++})-M(\Lambda_{c}^{+}) = 231.99\pm0.10\pm0.02$ MeV/$c^{2}$, and the decay widths $\Gamma(\Sigma_{c}(2455)^{0}) = 1.76\pm0.04^{+0.09}_{-0.21}$ MeV/$c^{2}$, $\Gamma(\Sigma_{c}(2455)^{++}) = 1.84\pm0.04^{+0.07}_{-0.20}$ MeV/$c^{2}$, $\Gamma(\Sigma_{c}(2520)^{0}) = 15.41\pm0.41^{+0.20}_{-0.32}$ MeV/$c^{2}$, $\Gamma(\Sigma_{c}(2520)^{++}) = 14.77\pm0.25^{+0.18}_{-0.30}$ MeV/$c^{2}$, where the first uncertainties are statistical and the second are systematic. The isospin mass splittings are measured to be $M(\Sigma_{c}(2455)^{++})-M(\Sigma_{c}(2455)^{0})=0.22\pm0.01\pm0.01$ MeV/$c^{2}$ and $M(\Sigma_{c}(2520)^{++})-M(\Sigma_{c}(2520)^{0})=0.01\pm0.15\pm0.03$ MeV/$c^{2}$. These results are the most precise to date.Comment: 13 pages, 4 figures, Submitted to PRD(RC

Measurements of the Υ(10860)\Upsilon(10860) and Υ(11020)\Upsilon(11020) resonances via σ(e+e−→Υ(nS)π+π−)\sigma(e^+e^-\rightarrow\Upsilon(n{\rm S})\pi^+\pi^-)

We report new measurements of the total cross sections for $e^+e^-\to \Upsilon(n{\rm S})\pi^+\pi^-$ ($n$ = 1, 2, 3) and $e^+e^-\to b\bar b$ from a high-luminosity fine scan of the region $\sqrt{s} = 10.63$-$11.05$ GeV with the Belle detector. We observe that the $\Upsilon(n{\rm S})\pi^+\pi^-$ spectra have little or no non-resonant component and extract from them the masses and widths of $\Upsilon(10860)$ and $\Upsilon(11020)$ and their relative phase. We find $M_{10860}=(10891.1\pm3.2^{+0.6}_{-1.7})$ MeV/$c^2$ and \Gamma_{10860}=(53.7^{+7.1}_{-5.6}\,^{+1.3}_{-5.4}) MeV and report first measurements M_{11020}=(10987.5^{+6.4}_{-2.5}\,^{+9.0}_{-2.1}) MeV/$c^2$, \Gamma_{11020}=(61^{+9}_{-19}\,^{+2}_{-20}) MeV, and \phi_{\rm 11020}-\phi_{\rm 10860} = (-1.0\pm0.4\,^{+1.4}_{-0.1}) rad.Comment: University of Cincinnati preprint UCHEP-15-01, submitted to Physical Review D - Rapid Communication

First study of \eta_c, \eta(1760) and X(1835) production via \eta'\pi^+\pi^- final states in two-photon collisions

The invariant mass spectrum of the \eta' \pi^+ \pi^- final state produced in two-photon collisions is obtained using a 673 fb^{-1} data sample collected in the vicinity of the \Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric-energy e^+e^- collider. We observe a clear signal of the \eta_c and measure its mass and width to be M(\eta_c)=(2982.7 +- 1.8(stat) +- 2.2(syst) +- 0.3(model)) MeV/c^2 and \Gamma(\eta_c) = (37.8^{+5.8}_{-5.3}(stat) +- 2.8(syst) +- 1.4(model)) MeV/c^2. The third error is an uncertainty due to possible interference between the \eta_c and a non-resonant component. We also report the first evidence for \eta(1760) decay to \eta' \pi^+ \pi^-; we find two solutions for its parameters, depending on the inclusion or not of the X(1835), whose existence is of marginal significance in our data. From a fit to the mass spectrum using coherent X(1835) and \eta(1760) resonant amplitudes, we set a 90% confidence level upper limit on the product \Gamma_{\gamma\gamma} \BR (\eta' \pi^+ \pi^-) for the X(1835).Comment: 13 pages, 7 figures, submitted to PR

Evidence for the decay B0->eta pi^0

We report a search for the charmless hadronic decay $B^0\to\eta \pi^0$ with a data sample corresponding to an integrated luminosity of 694 $\rm fb^{-1}$ containing $753\times10^6$ $B\bar{B}$ pairs. The data were collected by the Belle experiment running on the $\Upsilon(4S)$ resonance at the KEKB $e^+e^-$ collider. We measure a branching fraction $\mathcal{B}(B^0\to\eta\pi^0)=(4.1^{+1.7+0.5}_{-1.5-0.7})\times 10^{-7}$, where the first uncertainty is statistical and the second is systematic. Our measurement gives an upper limit of $\mathcal{B}(B^0\to\eta\pi^0)<6.5\times 10^{-7}$ at 90\% confidence level. The signal has a significance of $3.0$ standard deviations and constitutes the first evidence for this decay mode.Comment: 11 pages, 3 figures, 2 tables, submitted to Physical Review D(R

Control of Mitochondrial Morphology Through Differential Interactions of Mitochondrial Fusion and Fission Proteins

Mitochondria in mammals are organized into tubular networks that undergo frequent shape change. Mitochondrial fission and fusion are the main components mediating the mitochondrial shape change. Perturbation of the fission/fusion balance is associated with many disease conditions. However, underlying mechanisms of the fission/fusion balance are not well understood. Mitochondrial fission in mammals requires the dynamin-like protein DLP1/Drp1 that is recruited to the mitochondrial surface, possibly through the membrane-anchored protein Fis1 or Mff. Additional dynamin-related GTPases, mitofusin (Mfn) and OPA1, are associated with the outer and inner mitochondrial membranes, respectively, and mediate fusion of the respective membranes. In this study, we found that two heptad-repeat regions (HR1 and HR2) of Mfn2 interact with each other, and that Mfn2 also interacts with the fission protein DLP1. The association of the two heptad-repeats of Mfn2 is fusion inhibitory whereas a positive role of the Mfn2/DLP1 interaction in mitochondrial fusion is suggested. Our results imply that the differential binding of Mfn2-HR1 to HR2 and DLP1 regulates mitochondrial fusion and that DLP1 may act as a regulatory factor for efficient execution of both fusion and fission of mitochondria