Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease

Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD

Deuteron distribution in nuclei and the Levinger's factor

We compute the distribution of quasideuterons in doubly closed shell nuclei. The ground states of $^{16}$O and $^{40}$Ca are described in $ls$ coupling using a realistic hamiltonian including the Argonne $v_{8}^\prime$ and the Urbana IX models of two-- and three--nucleon potentials, respectively. The nuclear wave function contains central and tensor correlations, and correlated basis functions theory is used to evaluate the distribution of neutron-proton pairs, having the deuteron quantum numbers, as a function of their total momentum. By computing the number of deuteron--like pairs we are able to extract the Levinger's factor and compare to both the available experimental data and the predictions of the local density approximation, based on nuclear matter estimates. The agreement with the experiments is excellent, whereas the local density approximation is shown to sizably overestimate the Levinger's factor in the region of the medium nuclei.Comment: 26 pages, 8 figures, typeset using REVTe

Photon data shed new light upon the GDR spreading width in heavy nuclei

A global study of the electric dipole strength in and below the isovector giant dipole resonance (GDR) is presented for mass numbers A>80. It relies on the recently established remarkably good match between data for the nuclear photo effect to novel photon scattering data covering the region below the neutron emission threshold as well as by average resonance neutron capture (ARC). From the wide energy coverage of these data the correlation of the GDR spreading width with energy can be studied with remarkable accuracy. A clear sensitivity to details of the nuclear shape, i.e. the beta- and gamma-deformations, is demonstrated. Based hereon a new parameterization of the energy dependence of the nuclear electric-dipole strength is proposed which - with only two new parameters - allows to describe the dipole strength in all heavy nuclei with A>80. Although it differs significantly from previous parameterizations it holds for spherical, transitional, triaxial and well deformed nuclei. The GDR spreading width depends in a regular way on the respective resonance energy, but it is independent of the photon energy.Comment: accepted by Phys. Lett. B after minor modification

Elastic and Raman scattering of 9.0 and 11.4 MeV photons from Au, Dy and In

Monoenergetic photons between 8.8 and 11.4 MeV were scattered elastically and in elastically (Raman) from natural targets of Au, Dy and In.15 new cross sections were measured. Evidence is presented for a slight deformation in the 197Au nucleus, generally believed to be spherical. It is predicted, on the basis of these measurements, that the Giant Dipole Resonance of Dy is very similar to that of 160Gd. A narrow isolated resonance at 9.0 MeV is observed in In.Comment: 31 pages, 11 figure

Nuclear Anapole Moments

Nuclear anapole moments are parity-odd, time-reversal-even E1 moments of the electromagnetic current operator. Although the existence of this moment was recognized theoretically soon after the discovery of parity nonconservation (PNC), its experimental isolation was achieved only recently, when a new level of precision was reached in a measurement of the hyperfine dependence of atomic PNC in 133Cs. An important anapole moment bound in 205Tl also exists. In this paper, we present the details of the first calculation of these anapole moments in the framework commonly used in other studies of hadronic PNC, a meson exchange potential that includes long-range pion exchange and enough degrees of freedom to describe the five independent $S-P$ amplitudes induced by short-range interactions. The resulting contributions of pi-, rho-, and omega-exchange to the single-nucleon anapole moment, to parity admixtures in the nuclear ground state, and to PNC exchange currents are evaluated, using configuration-mixed shell-model wave functions. The experimental anapole moment constraints on the PNC meson-nucleon coupling constants are derived and compared with those from other tests of the hadronic weak interaction. While the bounds obtained from the anapole moment results are consistent with the broad ``reasonable ranges'' defined by theory, they are not in good agreement with the constraints from the other experiments. We explore possible explanations for the discrepancy and comment on the potential importance of new experiments.Comment: 53 pages; 10 figures; revtex; submitted to Phys Rev

The Role of Nucleons in Electromagnetic Emission Rates

Electromagnetic emission rates from a thermalized hadronic gas are important for the interpretation of dilepton signals from heavy-ion collisions. Although there is a consensus in the literature about rates for a pure meson gas, qualitative differences appear with a finite baryon density. We show this to be essentially due to the way in which the pi-N background is treated in regards to the nucleon resonances. Using a background constrained by unitarity and broken chiral symmetry, it is emphasized that the thermalized hadronic gas can be considered dilute.Comment: 9 pages, 7 figures, minor change

Identification and Characterization of Peripheral T-Cell Lymphoma-Associated SEREX Antigens

Peripheral T-cell lymphomas (PTCL) are generally less common and pursue a more aggressive clinical course than B-cell lymphomas, with the T-cell phenotype itself being a poor prognostic factor in adult non-Hodgkin lymphoma (NHL). With notable exceptions such as ALK+ anaplastic large cell lymphoma (ALCL, ALK+), the molecular abnormalities in PTCL remain poorly characterised. We had previously identified circulating antibodies to ALK in patients with ALCL, ALK+. Thus, as a strategy to identify potential antigens associated with the pathogenesis of PTCL, not otherwise specified (PTCL, NOS), we screened a testis cDNA library with sera from four PTCL, NOS patients using the SEREX (serological analysis of recombinant cDNA expression libraries) technique. We identified nine PTCL, NOS-associated antigens whose immunological reactivity was further investigated using sera from 52 B- and T-cell lymphoma patients and 17 normal controls. The centrosomal protein CEP250 was specifically recognised by patients sera and showed increased protein expression in cell lines derived from T-cell versus B-cell malignancies. TCEB3, BECN1, and two previously uncharacterised proteins, c14orf93 and ZBTB44, were preferentially recognised by patients' sera. Transcripts for all nine genes were identified in 39 cancer cell lines and the five genes encoding preferentially lymphoma-recognised antigens were widely expressed in normal tissues and mononuclear cell subsets. In summary, this study identifies novel molecules that are immunologically recognised in vivo by patients with PTCL, NOS. Future studies are needed to determine whether these tumor antigens play a role in the pathogenesis of PTCL

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required