Search

VGF mRNA is widely expressed in areas of the nervous system known to degenerate in Amyotrophic Lateral Sclerosis (ALS), including cerebral cortex, brainstem and spinal cord. Despite certain VGF alterations are reported in animal models, little information is available with respect to the ALS patients. We addressed VGF peptide changes in fibroblast cell cultures and in plasma obtained from ALS patients, in parallel with spinal cord and plasma samples from the G93A-SOD1 mouse model. Antisera specific for the C-terminal end of the human and mouse VGF proteins, respectively, were used in immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), while gel chromatography and HPLC/ESI-MS/MS were used to identify the VGF peptides present. Immunoreactive VGF C-terminus peptides were reduced in both fibroblast and plasma samples from ALS patients in an advanced stage of the disease. In the G93A-SOD1 mice, the same VGF peptides were also decreased in plasma in the late-symptomatic stage, while showing an earlier down-regulation in the spinal cord. In immunohistochemistry, a large number of gray matter structures were VGF C-terminus immunoreactive in control mice (including nerve terminals, axons and a few perikarya identified as motoneurons), with a striking reduction already in the pre-symptomatic stage. Through gel chromatography and spectrometry analysis, we identified one form likely to be the VGF precursor as well as peptides containing the NAPP- sequence in all tissues studied, while in the mice and fibroblasts, we revealed also AQEE- and TLQP- peptides. Taken together, selective VGF fragment depletion may participate in disease onset and/or progression of ALS.

Abstract Supersymmetric, magnetically charged (and possibly accelerating) black holes in AdS4 that uplift on Sasaki-Einstein manifolds Y 7 to M-theory have a dual matrix model description. The matrix model in turn arises by localization of the 3d N $$ \mathcal{N} $$ = 2 SCFTs, dual to the AdS4 vacuum, on the black hole horizon geometry, which is a Riemann surface Σ g (or a spindle Σ). We identify the imaginary part t of the continuously distributed eigenvalues in the matrix model, and their density function ρ(t), with natural geometric quantities associated with the M-theory circle action U(1) M on the near-horizon geometry AdS2 × Y 9, the internal space Y 9 being a Y 7 fibration over Σ g (or Σ). Moreover, we argue that the points where ρ ′ (t) is discontinuous match with the classical action of BPS probe M2-branes wrapping AdS2 and the M-theory circle. We illustrate our findings with the ABJM and ADHM theories, whose duals have Y 7 = S 7/ℤ k , and some of their flavoured variants corresponding to other toric Y 7.

Abstract We construct families of supersymmetric AdS3 × Y 7 and AdS3 × Y 8 solutions to type IIB string theory and M-theory, respectively. Here Y 7 is an S 5 fibration over Σ, while Y 8 is an S 4 fibration over Σ g × Σ, where Σ g is a Riemann surface of genus g > 1 and Σ is a two-dimensional orbifold known as a spindle. We interpret the solutions as near-horizon limits of N D3-branes wrapped on Σ and N M5-branes wrapped on Σ g × Σ, respectively. These are holographically dual to d = 2, (0, 2) SCFTs, and we show that the central charge and superconformal R-symmetry of the gravity solutions agree with dual field theory calculations.