Tributes to Professor Cyril A. Fox, Jr.

Cy Fox often forgets that he was supposed to be “only” an academic. For three decades, as he helped thousands of law students through the intricacies of the Rule in Shelley’s Case, or watched them calculate a “life in being plus twenty one years” for the Rule Against Perpetuities, he failed to appreciate that law school was supposed to be an amalgam of theory and confusion, not the place for his teaching law students about helping real people solve real life problems

Twist-controlled Resonant Tunnelling between Monolayer and Bilayer Graphene

We investigate the current-voltage characteristics of a field-effect tunnelling transistor comprised of both monolayer and bilayer graphene with well-aligned crystallographic axes, separated by three layers of hexagonal boron nitride. Using a self-consistent description of the device's electrostatic configuration we relate the current to three distinct tunable voltages across the system and hence produce a two-dimensional map of the I-V characteristics in the low energy regime. We show that the use of gates either side of the heterostructure offers a fine degree of control over the device's rich array of characteristics, as does varying the twist between the graphene electrodes.Comment: 5 pages including references and 3 figure

Neutralization of chemokines RANTES and MIG increases virus antigen expression and spinal cord pathology during Theiler's virus infection.

The role of chemokines during some viral infections is unpredictable because the inflammatory response regulated by these molecules can have two, contrasting effects-viral immunity and immunopathologic injury to host tissues. Using Theiler's virus infection of SJL mice as a model of this type of disease, we have investigated the roles of two chemokines-regulated on activation, normal T cell-expressed and secreted (RANTES) chemokine and monokine induced by IFN-gamma (MIG)-by treating mice with antisera that block lymphocyte migration. Control, infected mice showed virus persistence, mild inflammation and a small degree of demyelination in the white matter of the spinal cord at 6 weeks post-infection. Treatment of mice with RANTES antiserum starting at 2 weeks post-infection increased both viral antigen expression and the severity of inflammatory demyelination at 6 weeks post-infection. MIG antiserum increased the spread of virus and the proportion of spinal cord white matter with demyelination. Overall, viral antigen levels correlated strongly with the extent of pathology. At the RNA level, high virus expression was associated with low IL-2 and high IL-10 levels, and RANTES antiserum decreased the IL-2/IL-10 ratio. Our results suggest that RANTES and MIG participate in an immune response that attempts to restrict viral expression while limiting immunopathology and that anti-chemokine treatment poses the risk of exacerbating both conditions in the long term

Direct radiative capture of p-wave neutrons

The neutron direct radiative capture (DRC) process is investigated, highlighting the role of incident p-wave neutrons. A set of calculations is shown for the 12-C(n,gamma) process at incoming neutron energies up to 500 keV, a crucial region for astrophysics. The cross section for neutron capture leading to loosely bound s, p and d orbits of 13-C is well reproduced by the DRC model demonstrating the feasibility of using this reaction channel to study the properties of nuclear wave functions on and outside the nuclear surface. A sensitivity analysis of the results on the neutron-nucleus interaction is performed for incident s- as well as p-waves. It turned out that the DRC cross section for p-wave neutrons is insensitive to this interaction, contrary to the case of incident s-wave neutrons. PACS number(s): 25.40Lw,21.10Gv,23.40.HcComment: 16 pages, REVTeX file, PostScript file, .dvi fil

Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment.

Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b+ Ly6G+ neutrophils into the spinal cord. Targeting neutrophils resulted in a reduction in demyelination arguing for a role for these cells in myelin damage. Collectively, these findings emphasize that CXCL1-mediated attraction of neutrophils into the CNS augments demyelination suggesting that this signaling pathway may offer new targets for therapeutic intervention

The paucity of globular clusters around the field elliptical NGC 7507

Context. There is strong evidence that globular cluster systems (GCSs) of massive galaxies are largely assembled by infall/accretion processes. Therefore, we expect the GCSs of isolated elliptical galaxies to be poor. Although not completely isolated, NGC 7507 is a massive field elliptical galaxy with an apparently very low dark matter content. Aims. We determine the richness, the colour distribution, and the structural properties of the GCS of NGC 7507. Methods. We performed wide-field Washington photometry with data obtained with the MOSAIC II camera at the 4m-Blanco telescope (CTIO, Chile). Results. The GCS is very poor with SN ≈ 0.6. We identify three subpopulations with peaks at (C - T1) colours of 1.21, 1.42, and 1.72. The bluest population may represent the old, metal-poor component. This interpretation is supported by its shallow density profile. The red population is more concentrated, resembling the galaxy light. The intermediate-colour population is strongly peaked in colour, and we interpret this population as the signature of a starburst whose age depends on the metallicity, but should be quite old, since no signatures of a merger are identifiable. In addition, we find a main sequence in the stellar foreground population, which we attribute to the Sagittarius dwarf tidal stream. Conclusions. The extrordinarily poor GCS of NGC 7507, a massive elliptical galaxy, is an illustration of how important the environmental conditions are for producing rich GCSs.Instituto de Astrofísica de La PlataFacultad de Ciencias Astronómicas y Geofísica

Building and refinement of an in silico homology model of a novel G protein-coupled receptor: GPR35

Human GPR35 (hGPR35), a recently deorphanized Class A G-protein coupled receptor, has been shown to exhibit prominent expression in immune and gastrointestinal tissues, with additional expression in pancreatic islets, skeletal muscle, lung tissue, and the dorsal root ganglion. The rat GPR35 (rGPR35) analog, which has 72% sequence identity with human GPR35, has been shown to have expression in similar tissues as with human GPR35. GPR35 has been suggested to be involved in metabolism, heart failure, inflammation, asthma, a mental retardation syndrome associated with the deletion on 2q37.3, type II diabetes, as well as gastric cancer formation, making GPR35 a potential target for the treatment of multiple diseases. Both zaprinast, the well characterized cGMP-PDE inhibitor, and pamoic acid, a compound which the FDA has classified as an inactive compound, act as agonists at GPR35. However, interesting species differences have been found with these agonists and key mutations have also revealed differences between these two ligands. Pamoic acid is considerably lower in potency in rat GPR35, while zaprinast has increased efficacy in rat GPR35. Further, mutation studies suggest an increase in the potency of zaprinast in a human GPR35 R6.58A mutation. Pamoic acid, on the other hand shows similar potency to wild-type in this same mutant. To probe the molecular origins of these differences, three separate homology models, an active (R*) hGPR35, an R* hGPR35 R6.58A(240) mutant, and an R* rGPR35 model, were constructed and docking studies were performed with the aforementioned ligands. These studies revealed that the change in residue 5.43 (P5.43 in human; S5.43 in rat) alters the shape of the binding pocket for pamoic acid. In addition, arginines which contribute significantly to the interaction of pamoic acid in hGPR35 (R6.58 and R7.32) become uncharged residues (Q6.58 and S7.32) in rat GPR35. The increase of the potency of zaprinast in the hGPR35 R6.58A mutant receptor is due to the loss of bulk at position 6.58 (R6.58(240)¨ A6.58(240)), that allows for additional interactions with the ligand. The statistically equivalent potencies of pamoic acid for the wild-type and R6.58A(240) mutant hGPR35 receptors is due to the isoenergetic interchange of the direct interaction residue R6.58(240) with R7.32(255) in the R6.58(240)A mutant

Genetic Targeting of Adult Renshaw Cells Using a Calbindin 1 Destabilized Cre Allele for Intersection With Parvalbumin or Engrailed1

Renshaw cells (RCs) are one of the most studied spinal interneurons; however, their roles in motor control remain enigmatic in part due to the lack of experimental models to interfere with RC function, specifically in adults. To overcome this limitation, we leveraged the distinct temporal regulation of Calbindin (Calb1) expression in RCs to create genetic models for timed RC manipulation. We used a Calb1 allele expressing a destabilized Cre (dgCre) theoretically active only upon trimethoprim (TMP) administration. TMP timing and dose influenced RC targeting efficiency, which was highest within the first three postnatal weeks, but specificity was low with many other spinal neurons also targeted. In addition, dgCre showed TMP-independent activity resulting in spontaneous recombination events that accumulated with age. Combining Calb1-dgCre with Parvalbumin (Pvalb) or Engrailed1 (En1) Flpo alleles in dual conditional systems increased cellular and timing specificity. Under optimal conditions, Calb1-dgCre/Pvalb-Flpo mice targeted 90% of RCs and few dorsal horn neurons; Calb1-dgCre/En1-Flpo mice showed higher specificity, but only a maximum of 70% of RCs targeted. Both models targeted neurons throughout the brain. Restricted spinal expression was obtained by injecting intraspinally AAVs carrying dual conditional genes. These results describe the first models to genetically target RCs bypassing development