Misfolding of CasBrE SU is reversed by interactions with 4070A Env: implications for gammaretroviral neuropathogenesis

<p>Abstract</p> <p>Background</p> <p>CasBrE is a neurovirulent murine leukemia virus (MLV) capable of inducing paralytic disease with associated spongiform neurodegeneration. The neurovirulence of this virus has been genetically mapped to the surface expressed subunit (SU) of the <it>env </it>gene. However, CasBrE SU synthesized in the absence of the transmembrane subunit (TM) does not retain ecotropic receptor binding activity, indicating that folding of the receptor binding domain (RBD) requires this domain. Using a neural stem cell (NSC) based viral <it>trans </it>complementation approach to examine whether misfolded CasBrE SU retained neurovirulence, we observed CasBrE SU interaction with the "non-neurovirulent" amphotropic helper virus, 4070A which restored functional activity of CasBrE SU.</p> <p>Results</p> <p>Herein, we show that infection of NSCs expressing CasBrE SU with 4070A (CasES+4070A-NSCs) resulted in the redistribution of CasBrE SU from a strictly secreted product to include retention on the plasma membrane. Cell surface cross-linking analysis suggested that CasBrE SU membrane localization was due to interactions with 4070A Env. Viral particles produced from CasES+4070A-NSCS contained both CasBrE and 4070A gp70 Env proteins. These particles displayed ecotropic receptor-mediated infection, but were still 100-fold less efficient than CasE+4070A-NSC virus. Infectious center analysis showed CasBrE SU ecotropic transduction efficiencies approaching those of NSCs expressing full length CasBrE Env (CasE; SU+TM). In addition, CasBrE SU-4070A Env interactions resulted in robust ecotropic superinfection interference indicating near native intracellular SU interaction with its receptor, mCAT-1.</p> <p>Conclusions</p> <p>In this report we provided evidence that 4070A Env and CasBrE SU physically interact within NSCs leading to CasBrE SU retention on the plasma membrane, incorporation into viral particles, restoration of mCAT-1 binding, and capacity for initiation of TM-mediated fusion events. Thus, heterotropic Env-SU interactions facilitates CasBrE SU folding events that restore Env activity. These findings are consistent with the idea that one protein conformation acts as a folding scaffold or nucleus for a second protein of similar primary structure, a process reminiscent of prion formation. The implication is that template-based protein folding may represent an inherent feature of neuropathogenic proteins that extends to retroviral Envs.</p

Dissecting the Determinants of Neuropathogenesis of the Murine Oncornaviruses

Digitalitzat per Artypla

Family Psychoeducation in Clinical High Risk and First- Episode Psychosis

Seventy percent of those who will have an episode of psychosis will have done so by age 25. Data from clinical trials of intervention during the clinical high risk period of psychosis have determined that the mean age is in mid-adolescence, 16-18 years of age. For those reasons, early intervention inherently involves adolescents, and by extension their parents and other family members and supports. Regarding the type of intervention, it is relevant that the current empirically-derived standard of treatment for schizophrenia, as concluded by the Agency for Health Care Policy and Research survey of the treatment outcome literature, includes family psychoeducation, supported employment, assertive community treatment and antipsychotic medication,; i.e., a combination of psychosocial and pharmacologic interventions. Combinations of all four of these treatments, as in Family-aided Assertive Community Treatment (FACT), achieve very low rates of relapse, substantial reductions of symptoms and remarkable functional outcomes, particularly in the domain of competitive employment. Furthermore, a large comparative study of outcomes in community settings found that psychoeducational multifamily groups were more effective than single-family psychoeducation specifically in the first episode and in high-risk-for relapse cases, suggesting that particular psychosocial treatments may be especially effective in early phases of illness

Probing the isospin dependence of the in-medium nucleon-nucleon cross sections with radioactive beams

Within a transport model we search for potential probes of the isospin dependence of the in-medium nucleon-nucleon (NN) cross sections. Traditional measures of the nuclear stopping power are found sensitive to the magnitude but they are ambiguous for determining the isospin dependence of the in-medium NN cross sections. It is shown that isospin tracers, such as the neutron/proton ratio of free nucleons, at backward rapidities/angles in nuclear reactions induced by radioactive beams in inverse kinematics is a sensitive probe of the isospin dependence of the in-medium NN cross sections. At forward rapidities/angles, on the other hand, they are more sensitive to the density dependence of the symmetry energy. Measurements of the rapidity/angular dependence of the isospin transport in nuclear reactions will enable a better understanding of the isospin dependence of in-medium nuclear effective interactions.Comment: 19 pages including 7 figures, submitted to Phys. Rev.