Morphological and Behavioral Changes in the Pathogenesis of a Novel Mouse Model of Communicating Hydrocephalus

The Ro1 model of hydrocephalus represents an excellent model for studying the pathogenesis of hydrocephalus due to its complete penetrance and inducibility, enabling the investigation of the earliest cellular and histological changes in hydrocephalus prior to overt pathology. Hematoxylin and eosin staining, immunofluorescence and electron microscopy were used to characterize the histopathological events of hydrocephalus in this model. Additionally, a broad battery of behavioral tests was used to investigate behavioral changes in the Ro1 model of hydrocephalus. The earliest histological changes observed in this model were ventriculomegaly and disorganization of the ependymal lining of the aqueduct of Sylvius, which occurred concomitantly. Ventriculomegaly led to thinning of the ependyma, which was associated with periventricular edema and areas of the ventricular wall void of cilia and microvilli. Ependymal denudation was subsequent to severe ventriculomegaly, suggesting that it is an effect, rather than a cause, of hydrocephalus in the Ro1 model. Additionally, there was no closure of the aqueduct of Sylvius or any blockages within the ventricular system, even with severe ventriculomegaly, suggesting that the Ro1 model represents a model of communicating hydrocephalus. Interestingly, even with severe ventriculomegaly, there were no behavioral changes, suggesting that the brain is able to compensate for the structural changes that occur in the pathogenesis of hydrocephalus if the disorder progresses at a sufficiently slow rate

Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor

G protein–coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4b receptor, a GPCR with high constitutive Gs signaling and strong ligand-induced G-protein activation of the Gs and Gs/q pathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gs signaling, but only a few (e.g., zacopride) also induced signaling via the Gq pathway. Zacopride-induced Gq signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2C receptor. Additional point mutations (D66A and D66N) blocked constitutive Gs signaling and lowered ligand-induced Gq signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1A conferred ligand-mediated Gi signaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gs or Gq pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection

Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas

Glioblastomas are among the most incurable cancers. Our past findings indicated that glioblastoma cells, but not neurons or glia, require the transcription factor ATF5 (activating transcription factor 5) for survival. However, it was unknown whether interference with ATF5 function can prevent or promote regression/eradication of malignant gliomas in vivo. To address this issue, we created a mouse model by crossing a human glial fibrillary acidic protein (GFAP) promoter-tetracycline transactivator mouse line with tetracycline operon-dominant negative-ATF5 (d/n-ATF5) mice to establish bi-transgenic mice. In this model, d/n-ATF5 expression is controlled by doxycycline and the promoter for GFAP, a marker for stem/progenitor cells as well as gliomas. Endogenous gliomas were produced with high efficiency by retroviral delivery of platelet-derived growth factor (PDGF)-B and p53-short hairpin RNA (shRNA) in adult bi-transgenic mice in which expression of d/n-ATF5 was spatially and temporally regulated. Induction of d/n-ATF5 before delivery of PDGF-B/p53-shRNA virus greatly reduced the proportion of mice that formed tumors. Moreover, d/n-ATF5 induction after tumor formation led to regression/eradication of detectable gliomas without evident damage to normal brain cells in all 24 mice assessed

Event-by-event correlations between Λ\Lambda (Λˉ\bar{\Lambda}) hyperon global polarization and handedness with charged hadron azimuthal separation in Au+Au collisions at sNN=27 GeV\sqrt{s_{\text{NN}}} = 27 \text{ GeV} from STAR

Global polarizations ($P$) of $\Lambda$ ($\bar{\Lambda}$) hyperons have been observed in non-central heavy-ion collisions. The strong magnetic field primarily created by the spectator protons in such collisions would split the $\Lambda$ and $\bar{\Lambda}$ global polarizations ($\Delta P = P_{\Lambda} - P_{\bar{\Lambda}} < 0$). Additionally, quantum chromodynamics (QCD) predicts topological charge fluctuations in vacuum, resulting in a chirality imbalance or parity violation in a local domain. This would give rise to an imbalance ($\Delta n = \frac{N_{\text{L}} - N_{\text{R}}}{\langle N_{\text{L}} + N_{\text{R}} \rangle} \neq 0$) between left- and right-handed $\Lambda$ ($\bar{\Lambda}$) as well as a charge separation along the magnetic field, referred to as the chiral magnetic effect (CME). This charge separation can be characterized by the parity-even azimuthal correlator ($\Delta\gamma$) and parity-odd azimuthal harmonic observable ($\Delta a_{1}$). Measurements of $\Delta P$, $\Delta\gamma$, and $\Delta a_{1}$ have not led to definitive conclusions concerning the CME or the magnetic field, and $\Delta n$ has not been measured previously. Correlations among these observables may reveal new insights. This paper reports measurements of correlation between $\Delta n$ and $\Delta a_{1}$, which is sensitive to chirality fluctuations, and correlation between $\Delta P$ and $\Delta\gamma$ sensitive to magnetic field in Au+Au collisions at 27 GeV. For both measurements, no correlations have been observed beyond statistical fluctuations.Comment: 10 pages, 10 figures; paper from the STAR Collaboratio

Measurement of electrons from open heavy-flavor hadron decays in Au+Au collisions at sNN=200\sqrt{s_{\rm NN}}=200 GeV with the STAR detector

We report a new measurement of the production of electrons from open heavy-flavor hadron decays (HFEs) at mid-rapidity ($|y|<$ 0.7) in Au+Au collisions at $\sqrt{s_{\rm NN}}=200$ GeV. Invariant yields of HFEs are measured for the transverse momentum range of $3.5 < p_{\rm T} < 9$ GeV/$c$ in various configurations of the collision geometry. The HFE yields in head-on Au+Au collisions are suppressed by approximately a factor of 2 compared to that in $p$+$p$ collisions scaled by the average number of binary collisions, indicating strong interactions between heavy quarks and the hot and dense medium created in heavy-ion collisions. Comparison of these results with models provides additional tests of theoretical calculations of heavy quark energy loss in the quark-gluon plasma

Measurement of Λ4H\rm ^4_{\Lambda}H and Λ4He\rm ^4_{\Lambda}He binding energy in Au+Au collisions at sNN\sqrt{s_\mathrm{NN}} = 3 GeV

Measurements of mass and $\Lambda$ binding energy of $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$ in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}=3$ GeV are presented, with an aim to address the charge symmetry breaking (CSB) problem in hypernuclei systems with atomic number A = 4. The $\Lambda$ binding energies are measured to be $\rm 2.22\pm0.06(stat.) \pm0.14(syst.)$ MeV and $\rm 2.38\pm0.13(stat.) \pm0.12(syst.)$ MeV for $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$, respectively. The measured $\Lambda$ binding-energy difference is $\rm 0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV for ground states. Combined with the $\gamma$-ray transition energies, the binding-energy difference for excited states is $\rm -0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV, which is negative and comparable to the value of the ground states within uncertainties. These new measurements on the $\Lambda$ binding-energy difference in A = 4 hypernuclei systems are consistent with the theoretical calculations that result in $\rm \Delta B_{\Lambda}^4(1_{exc}^{+})\approx -\Delta B_{\Lambda}^4(0_{g.s.}^{+})<0$ and present a new method for the study of CSB effect using relativistic heavy-ion collisions.Comment: 8 pages, 5 figure

Search for the Chiral Magnetic Effect in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV with the STAR forward Event Plane Detectors

A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at $\sqrt{s_{_{\rm{NN}}}}=27$ GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity $|\eta|<1.0$ and at forward rapidity $2.1 < |\eta|<5.1$. We compare the results based on the directed flow plane ($\Psi_1$) at forward rapidity and the elliptic flow plane ($\Psi_2$) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to $\Psi_1$ than to $\Psi_2$, while a flow driven background scenario would lead to a consistent result for both event planes[1,2]. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.Comment: main: 8 pages, 5 figures; supplementary material: 2 pages, 1 figur

Search for the chiral magnetic effect via charge-dependent azimuthal correlations relative to spectator and participant planes in Au+Au collisions at sNN\sqrt{s_{NN}} = 200 GeV

The chiral magnetic effect (CME) refers to charge separation along a strong magnetic field due to imbalanced chirality of quarks in local parity and charge-parity violating domains in quantum chromodynamics. The experimental measurement of the charge separation is made difficult by the presence of a major background from elliptic azimuthal anisotropy. This background and the CME signal have different sensitivities to the spectator and participant planes, and could thus be determined by measurements with respect to these planes. We report such measurements in Au+Au collisions at a nucleon-nucleon center-of-mass energy of 200 GeV at the Relativistic Heavy-Ion Collider. It is found that the charge separation, with the flow background removed, is consistent with zero in peripheral (large impact parameter) collisions. Some indication of finite CME signals is seen with a significance of 1--3 standard deviations in mid-central (intermediate impact parameter) collisions. Significant residual background effects may, however, still be present.Comment: 8 pages, 3 figure