Vascular derived endothelin receptor A controls endothelin-induced retinal ganglion cell death.

Endothelin (EDN, also known as ET) signaling has been suggested to be an important mediator of retinal ganglion cell (RGC) death in glaucoma. Antagonism of EDN receptors (EDNRA and EDNRB, also known as ET-A and ET-B) prevented RGC death in mouse models of chronic ocular hypertension, and intravitreal injection of EDN ligand was sufficient to drive RGC death. However, it remains unclear which cell types EDN ligands directly affect to elicit RGC death. Multiple cell types in the retina and optic nerve express EDNRA and EDNRB and thus could respond to EDN ligands in the context of glaucoma. Here, we systematically deleted Edn receptors from specific cell types to identify the critical EDN receptor mediating RGC death in vivo. Deletion of both Ednra and Ednrb from retinal neurons (including RGCs) and macroglia did not prevent RGC loss after exposure to EDN1 ligands, suggesting EDN1 ligands cause RGC death via an indirect mechanism involving a secondary cell type. Deletion of Ednra from the full body, and then specifically from vascular mural cells, prevented EDN1-induced vasoconstriction and RGC death. Together, these data suggest EDN ligands cause RGC death via a mechanism initiated by vascular mural cells. It is possible RGC death is a consequence of vascular mural cell-induced vasoconstriction and its pathological sequelae. These results highlight the potential importance of neurovascular dysfunction in glaucoma

First determination of the CPCP content of D→π+π−π+π−D \to \pi^+\pi^-\pi^+\pi^- and updated determination of the CPCP contents of D→π+π−π0D \to \pi^+\pi^-\pi^0 and D→K+K−π0D \to K^+K^-\pi^0

Quantum-correlated $\psi(3770) \to D\bar{D}$ decays collected by the CLEO-c experiment are used to perform a first measurement of $F_+^{4\pi}$, the fractional $CP$-even content of the self-conjugate decay $D \to \pi^+\pi^-\pi^+\pi^-$, obtaining a value of $0.737 \pm 0.028$. An important input to the measurement comes from the use of $D \to K^0_{\rm S}\pi^+\pi^-$ and $D \to K^0_{\rm L}\pi^+\pi^-$ decays to tag the signal mode. This same technique is applied to the channels $D \to\pi^+\pi^-\pi^0$ and $D \to K^+K^-\pi^0$, yielding $F_+^{\pi\pi\pi^0} = 1.014 \pm 0.045 \pm 0.022$ and $F_+^{KK\pi^0} = 0.734 \pm 0.106 \pm 0.054$, where the first uncertainty is statistical and the second systematic. These measurements are consistent with those of an earlier analysis, based on $CP$-eigenstate tags, and can be combined to give values of $F_+^{\pi\pi\pi^0} = 0.973 \pm 0.017$ and $F_+^{KK\pi^0} = 0.732 \pm 0.055$. The results will enable the three modes to be included in a model-independent manner in measurements of the unitarity triangle angle $\gamma$ using $B^\mp \to DK^\mp$ decays, and in time-dependent studies of $CP$ violation and mixing in the $D\bar{D}$ system.Comment: Minor revisions following journal acceptanc

Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation.

Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun-/-), Ddit3 null (Ddit3-/-), and Ddit3-/-Jun-/- mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation

Transcriptional control of retinal ganglion cell death after axonal injury.

Injury to the axons of retinal ganglion cells (RGCs) is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target of the c-Jun N-terminal kinases, JNKs) and DDIT3/CHOP (a mediator of the endoplasmic reticulum stress response) have been shown to control the majority of proapoptotic signaling after mechanical axonal injury in RGCs and in other models of neurodegeneration. The downstream transcriptional networks controlled by JUN and DDIT3, which are critical for RGC death, however, are not well defined. To determine these networks, RNA was isolated from the retinas of wild-type mice and mice deficient in Jun, Ddit3, and both Jun and Ddit3 three days after mechanical optic nerve crush injury (CONC). RNA-sequencing data analysis was performed and immunohistochemistry was used to validate potential transcriptional signaling changes after axonal injury. This study identified downstream transcriptional changes after injury including both neuronal survival and proinflammatory signaling that were attenuated to differing degrees by loss of Ddit3, Jun, and Ddit3/Jun. These data suggest proinflammatory signaling in the retina might be secondary to activation of pro-death pathways in RGCs after acute axonal injury. These results determine the downstream transcriptional networks important for apoptotic signaling which may be important for ordering and staging the pro-degenerative signals after mechanical axonal injury

Coefficient Functions and Open Charm Production in Deep Inelastic Scattering

It is shown that the problem of double counting in open charm production in DIS can be solved by using the expression for DIS coefficient functions in terms of 2PI diagramsComment: 11 pages, REVTeX, no figure

Improved fluid dynamics similarity, analysis and verification Annual report, 29 Jun. 1965 - 28 Jun. 1966

Fluid mechanics and dynamic reactions in liquid flow, single-phase flow, and two-phase flo

First determination of the CP content of D->pi+pi-pi0 and D->K+K-pi0

Quantum-correlated psi(3770)->DDbar decays collected by the CLEO-c experiment are used to perform first measurements of F+, the fractional CP-even content of the self-conjugate decays D->pi+pi-pi0 and D->K+K-pi0. Values of 0.968 +/- 0.017 +/- 0.006 and 0.731 +/- 0.058 +/- 0.021 are obtained for pi+pi-pi0 and K+K-pi0, respectively. It is demonstrated how modes of this sort can be cleanly included in measurements of the unitarity triangle angle gamma using B+/- -> D K+/- decays. The high CP-even content of D -> pi+pi-pi0, in particular, makes this a promising mode for improving the precision on gamma.Comment: 18 pages, 4 figures, submitted to Phys. Lett.

Branching of the Falkner-Skan solutions for λ < 0

The Falkner-Skan equation f'" + ff" + λ(1 - f'^2) = 0, f(0) = f'(0) = 0, is discussed for λ < 0. Two types of problems, one with f'(∞) = 1 and another with f'(∞) = -1, are considered. For λ = 0- a close relation between these two types is found. For λ < -1 both types of problem allow multiple solutions which may be distinguished by an integer N denoting the number of zeros of f' - 1. The numerical results indicate that the solution branches with f'(∞) = 1 and those with f'(∞) = -1 tend towards a common limit curve as N increases indefinitely. Finally a periodic solution, existing for λ < -1, is presented.