Pushing electrons daniel p weeks pdf editor

PML has вЂre-emergedвЂ™ as a complication of immunomodulatory therapies, such as natalizumab (О±4 integrin humanized mAb) for treatment of relapsing-remitting multiple sclerosis (RRMS), rituximab (CD20 humanized mAb) for chronic lymphocytic leukemia and non-HodgkinвЂ™s lymphoma, and efalizumab (LFA-1 humanized mAb) for severe plaque psoriasis ( Carson et al., 2009 Kleinschmidt-DeMasters and Tyler, 2005 Kothary et al., 2011 Langer-Gould et al., 2005 Schwab et al., 2012 Van Assche et al., 2005). PML was originally described as a rare complication of hematological malignancies and its incidence dramatically increased in the pre-HAART AIDS epoch ( Astrom et al., 1958 Berger et al., 1987 Krupp et al., 1985). Immunological perturbations are a necessary antecedent for progressive multifocal leukoencephalopathy (PML), a fatal demyelinating brain disease caused by JCPyV ( Haley and Atwood, 2017). JC polyomavirus (JCPyV) is a prevalent member of the human virome ( Kamminga et al., 2018 Viscidi et al., 2011). The human virome is composed of a sizeable number of persistent viruses whose pathogenicity is restrained by a healthy adaptive immune system ( Virgin et al., 2009). Viruses causing persistent infections also acquire mutations that evade nAbs ( Ciurea et al., 2000 Inuzuka et al., 2018 Kinchen et al., 2018 Salpini et al., 2015 Wei et al., 2003). Seasonal influenza vaccinations are necessitated by the emergence of influenza A virus subtypes with mutations in hemagglutinin and neuraminidase capsid proteins that handicap neutralization by virus-specific antibodies ( Bedford et al., 2015 Hensley et al., 2009 Petrova and Russell, 2018). The humoral immune response is critical for controlling acute and persistent viral infections evasion of the neutralizing antibody (nAb) response often underlies virus-mediated morbidity and mortality. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation. The structure revealed the mechanism of mAb evasion. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Г… resolution. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response.

A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies.

Pushing electrons daniel p weeks pdf editor