Vice President Cheney\u27s Unused Resignation Letter

Resignation letter prepared by Vice President Dick Cheney for his chief of staff to deliver to President George W. Bush should Cheney become incapacitated. The letter was never delivered. It is accompanied by a memo written by Cheney\u27s chief of staff, David Addington, explaining the purpose of the resignation letter. Securing this document was a joint effort of Roy E. Brownell II and John Rogan.https://ir.lawnet.fordham.edu/twentyfifth_amendment_executive_materials/1015/thumbnail.jp

The Vice President-More than an Afterthought?

A round-table discussion among former U.S. Vice President Richard B. Cheney, Caruso Family Professor of Law and retired U.S. Ambassador Douglas Kmiec, and former U.S. Attorney General Edwin Meese III considered the practical implications of conceiving the Vice President as a legislative officer, an executive officer, or both. It was noted that until the second half of the twentieth century, the Office of the Vice President was conceived as legislative. Funding for the Office appeared in budget lines relating to Congress and physically, the Vice President’s office was in the Capitol. Beginning with Walter Mondale’s service as Vice President, presidents have been delegating increasing executive authority, seeing the Vice President as a “deputy president.” Perhaps the most aggressive and influential of the modern “deputy presidents” was Vice President Cheney himself. Attorney General Meese concurred and saw this as positive. Ambassador Kmiec was less approving, encouraging Vice President Cheney and Attorney General Meese to contemplate the benefits that a dual-natured legislative–executive Vice President supplies to maintaining a workable government. The capacity of the Vice President to assert independence, as late Justice Scalia explained in an Office of Legal Counsel opinion, is unique. Unlike members of the Cabinet, the Vice President is not removable by the President, and thus, the Vice President can use his dual nature to advance executive–legislative compromise. Vice President Cheney’s reliance upon his significant, but personal, legislative experience prior to his vice presidency to facilitate executive–legislative bargaining suggests qualities that presidential nominees might consider more directly in vice presidential selection, and not just geographic complementarity and ideological compatibility. While it has been commonplace to think of the vice presidential office as “an afterthought” borrowed from state charters at the time of the founding, this dialogue suggests how a vice president with a foot in each of the Legislative and Executive Branches can assist in overcoming dysfunctional periods when partisan division is great

Compact Nuclei in Galaxies at Moderate Redshift:II. Their Nature and Implications for the AGN Luminosity Function

This study explores the space density and properties of active galaxies to z=0.8. We have investigated the frequency and nature of unresolved nuclei in galaxies at moderate redshift as indicators of nuclear activity such as Active Galactic Nuclei (AGN) or starbursts. Candidates are selected by fitting imaged galaxies with multi-component models using maximum likelihood estimate techniques to determine the best model fit. We select those galaxies requiring an unresolved point-source component in the galaxy nucleus, in addition to a disk and/or bulge component, to adequately model the galaxy light. We have searched 70 WFPC2 images primarily from the Medium Deep Survey for galaxies containing compact nuclei. In our survey of 1033 galaxies, the fraction containing an unresolved nuclear component greater than 5% of the total galaxy light is 9+/-1% corrected for incompleteness. In this second of two papers in this series, we discuss the nature of the compact nuclei and their hosts. We present the upper limit luminosity function (LF) for low-luminosity AGN (LLAGN) in two redshift bins to z=0.8. Mild number density evolution is detected for nuclei at -18 -16 and this flatness, combined with the increase in number density, is inconsistent with pure luminosity evolution. Based on the amount of density evolution observed for these objects, we find that almost all present-day spiral galaxies could have hosted a LLAGN at some point in their lives. We also comment on the likely contribution of these compact nuclei to the soft X-ray background.Comment: 50 pages, 14 figures, to appear in ApJ, April 199

A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase

ABSTRACT The signaling molecule cyclic diguanylate (c-di-GMP) mediates physiological adaptation to extracellular stimuli in a wide range of bacteria. The complex metabolic pathways governing c-di-GMP synthesis and degradation are highly regulated, but the specific cues that impact c-di-GMP signaling are largely unknown. In the intestinal pathogen Clostridium difficile , c-di-GMP inhibits flagellar motility and toxin production and promotes pilus-dependent biofilm formation, but no specific biological functions have been ascribed to any of the individual c-di-GMP synthases or phosphodiesterases (PDEs). Here, we report the functional and biochemical characterization of a c-di-GMP PDE, PdcA, 1 of 37 confirmed or putative c-di-GMP metabolism proteins in C. difficile 630. Our studies reveal that pdcA transcription is controlled by the nutrient-regulated transcriptional regulator CodY and accordingly increases during stationary phase. In addition, PdcA PDE activity is allosterically regulated by GTP, further linking c-di-GMP levels to nutrient availability. Mutation of pdcA increased biofilm formation and reduced toxin biosynthesis without affecting swimming motility or global intracellular c-di-GMP. Analysis of the transcriptional response to pdcA mutation indicates that PdcA-dependent phenotypes manifest during stationary phase, consistent with regulation by CodY. These results demonstrate that inactivation of this single PDE gene is sufficient to impact multiple c-di-GMP-dependent phenotypes, including the production of major virulence factors, and suggest a link between c-di-GMP signaling and nutrient availability

A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production During Stationary Phase

The signaling molecule cyclic diguanylate (c-di-GMP) mediates physiological adaptation to extracellular stimuli in a wide range of bacteria. The complex metabolic pathways governing c-di-GMP synthesis and degradation are highly regulated, but the specific cues that impact c-di-GMP signaling are largely unknown. In the intestinal pathogen Clostridium difficile, c-di-GMP inhibits flagellar motility and toxin production and promotes pilus-dependent biofilm formation, but no specific biological functions have been ascribed to any of the individual c-di-GMP synthases or phosphodiesterases (PDEs). Here, we report the functional and biochemical characterization of a c-di-GMP PDE, PdcA, 1 of 37 confirmed or putative c-di-GMP metabolism proteins in C. difficile 630. Our studies reveal that pdcA transcription is controlled by the nutrient-regulated transcriptional regulator CodY and accordingly increases during stationary phase. In addition, PdcA PDE activity is allosterically regulated by GTP, further linking c-di-GMP levels to nutrient availability. Mutation of pdcA increased biofilm formation and reduced toxin biosynthesis without affecting swimming motility or global intracellular c-di-GMP. Analysis of the transcriptional response to pdcA mutation indicates that PdcA-dependent phenotypes manifest during stationary phase, consistent with regulation by CodY. These results demonstrate that inactivation of this single PDE gene is sufficient to impact multiple c-di-GMP-dependent phenotypes, including the production of major virulence factors, and suggest a link between c-di-GMP signaling and nutrient availability

Sequential roles for myosin-X in BMP6-dependent filopodial extension, migration, and activation of BMP receptors

Endothelial cell migration is an important step during angiogenesis, and its dysregulation contributes to aberrant neovascularization. The bone morphogenetic proteins (BMPs) are potent stimulators of cell migration and angiogenesis. Using microarray analyses, we find that myosin-X (Myo10) is a BMP target gene. In endothelial cells, BMP6-induced Myo10 localizes in filopodia, and BMP-dependent filopodial assembly decreases when Myo10 expression is reduced. Likewise, cellular alignment and directional migration induced by BMP6 are Myo10 dependent. Surprisingly, we find that Myo10 and BMP6 receptor ALK6 colocalize in a BMP6-dependent fashion. ALK6 translocates into filopodia after BMP6 stimulation, and both ALK6 and Myo10 possess intrafilopodial motility. Additionally, Myo10 is required for BMP6-dependent Smad activation, indicating that in addition to its function in filopodial assembly, Myo10 also participates in a requisite amplification loop for BMP signaling. Our data indicate that Myo10 is required to guide endothelial migration toward BMP6 gradients via the regulation of filopodial function and amplification of BMP signals

Myo10 in brain: developmental regulation, identification of a headless isoform and dynamics in neurons

Although Myo10 (myosin-X) is an unconventional myosin associated with filopodia, little is known about its isoforms and roles in the nervous system. We report here that, in addition to full-length Myo10, brain expresses a shorter form of Myo10 that lacks a myosin head domain. This ;headless' Myo10 is thus unable to function as a molecular motor, but is otherwise identical to full-length Myo10 and, like it, contains three pleckstrin homology (PH) domains, a myosin-tail homology 4 (MyTH4) domain, and a band-4.1/ezrin/radixin/moesin (FERM) domain. Immunoblotting demonstrates that both full-length and headless Myo10 exhibit dramatic developmental regulation in mouse brain. Immunofluorescence with an antibody that detects both isoforms demonstrates that Myo10 is expressed in neurons, such as Purkinje cells, as well as non-neuronal cells, such as astrocytes and ependymal cells. CAD cells, a neuronal cell line, express both full-length and headless Myo10, and this endogenous Myo10 is present in cell bodies, neurites, growth cones and the tips of filopodia. To investigate the dynamics of the two forms of Myo10 in neurons, CAD cells were transfected with GFP constructs corresponding to full-length or headless Myo10. Only full-length Myo10 localizes to filopodial tips and undergoes intrafilopodial motility, demonstrating that the motor domain is necessary for these activities. Live cell imaging also reveals that full-length Myo10 localizes to the tips of neuronal filopodia as they explore and interact with their surroundings, suggesting that this myosin has a role in neuronal actin dynamics

Myosin Vc Interacts with Rab32 and Rab38 Proteins and Works in the Biogenesis and Secretion of Melanosomes

Class V myosins are actin-based motors with conserved functions in vesicle and organelle trafficking. Herein we report the discovery of a function for Myosin Vc in melanosome biogenesis as an effector of melanosome-associated Rab GTPases. We isolated Myosin Vc in a yeast two-hybrid screening for proteins that interact with Rab38, a Rab protein involved in the biogenesis of melanosomes and other lysosome-related organelles. Rab38 and its close homolog Rab32 bind to Myosin Vc but not to Myosin Va or Myosin Vb. Binding depends on residues in the switch II region of Rab32 and Rab38 and regions of the Myosin Vc coiled-coil tail domain. Myosin Vc also interacts with Rab7a and Rab8a but not with Rab11, Rab17, and Rab27. Although Myosin Vc is not particularly abundant on pigmented melanosomes, its knockdown in MNT-1 melanocytes caused defects in the trafficking of integral membrane proteins to melanosomes with substantially increased surface expression of Tyrp1, nearly complete loss of Tyrp2, and significant Vamp7 mislocalization. Knockdown of Myosin Vc in MNT-1 cells more than doubled the abundance of pigmented melanosomes but did not change the number of unpigmented melanosomes. Together the data demonstrate a novel role for Myosin Vc in melanosome biogenesis and secretion

Myosin-X facilitates Shigella-induced membrane protrusions and cell-to-cell spread

The intracellular pathogen Shigella flexneri forms membrane protrusions to spread from cell to cell. As protrusions form, myosin-X (Myo10) localizes to Shigella. Electron micrographs of immunogold-labelled Shigella-infected HeLa cells reveal that Myo10 concentrates at the bases and along the sides of bacteria within membrane protrusions. Time-lapse video microscopy shows that a full-length Myo10 GFP-construct cycles along the sides of Shigella within the membrane protrusions as these structures progressively lengthen. RNAi knock-down of Myo10 is associated with shorter protrusions with thicker stalks, and causes a >80% decrease in confluent cell plaque formation. Myo10 also concentrates in membrane protrusions formed by another intracellular bacteria, Listeria, and knock-down of Myo10 also impairs Listeria plaque formation. In Cos7 cells (contain low concentrations of Myo10), the expression of full-length Myo10 nearly doubles Shigella-induced protrusion length, and lengthening requires the head domain, as well as the tail-PH domain, but not the FERM domain. The GFP-Myo10-HMM domain localizes to the sides of Shigella within membrane protrusions and the GFP-Myo10-PH domain localizes to host cell membranes. We conclude that Myo10 generates the force to enhance bacterial-induced protrusions by binding its head region to actin filaments and its PH tail domain to the peripheral membrane