Intranasally inoculated neurotropic influenza viruses in mice infect not only the respiratory tract but also the central nervous system (CNS), mainly the brain stem. Previous studies suggested that the route of invasion of virus into the CNS was via the peripheral nervous system, especially the vagus nerve. To evaluate the transvagal transmission of the virus, we intranasally inoculated unilaterally vagectomized mice with a virulent influenza virus (strain 24a5b) and examined the distribution of the viral protein and genome by immunohistochemistry and in situ hybridization over time. An asymmetric distribution of viral antigens was observed between vagal (nodose) ganglia: viral antigen was detected in the vagal ganglion of the vagectomized side 2 days later than in the vagal ganglion of the intact side. The virus was apparently transported from the respiratory mucosa to the CNS directly and decussately via the vagus nerve and centrifugally to the vagal ganglion of the vagectomized side. The results of this study, thus, demonstrate that neurotropic influenza virus travels to the CNS mainly via the vagus nerve.

Virus infections can result in a range of cellular injuries and commonly this involves both the plasma and intracellular membranes, resulting in enhanced permeability. Viroporins are a group of proteins that interact with plasma membranes modifying permeability and can promote the release of viral particles. While these proteins are not essential for virus replication, their activity certainly promotes virus growth. Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease resulting from lytic infection of oligodendrocytes by the polyomavirus JC virus (JCV). The genome of JCV encodes six major proteins including a small auxiliary protein known as agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to viral propagation at various stages in the replication cycle, including transcription, translation, processing of late viral proteins, assembly of virions, and viral propagation. Previous studies from our and other laboratories have indicated that JCV agnoprotein plays an important, although as yet incompletely understood role in the propagation of JCV. Here, we demonstrate that agnoprotein possesses properties commonly associated with viroporins. Our findings demonstrate that: (i) A deletion mutant of agnoprotein is defective in virion release and viral propagation; (ii) Agnoprotein localizes to the ER early in infection, but is also found at the plasma membrane late in infection; (iii) Agnoprotein is an integral membrane protein and forms homo-oligomers; (iv) Agnoprotein enhances permeability of cells to the translation inhibitor hygromycin B; (v) Agnoprotein induces the influx of extracellular Ca2+; (vi) The basic residues at amino acid positions 8 and 9 of agnoprotein key are determinants of the viroporin activity. The viroporin-like properties of agnoprotein result in increased membrane permeability and alterations in intracellular Ca2+ homeostasis leading to membrane dysfunction and enhancement of virus release.

For a finite group G acting on a smooth projective variety X, we construct two new G-equivariant rings: first the stringy K-theory of X, and second the stringy cohomology of X. For a smooth Deligne-Mumford stack Y we also construct a new ring called the full orbifold K-theory of Y. For a global quotient Y=[X/G], the ring of G-invariants of the stringy K-theory of X is a subalgebra of the full orbifold K-theory of the the stack Y and is linearly isomorphic to the ``orbifold K-theory'' of Adem-Ruan (and hence Atiyah-Segal), but carries a different, ``quantum,'' product, which respects the natural group grading. We prove there is a ring isomorphism, the stringy Chern character, from stringy K-theory to stringy cohomology, and a ring homomorphism from full orbifold K-theory to Chen-Ruan orbifold cohomology. These Chern characters satisfy Grothendieck-Riemann-Roch for etale maps. We prove that stringy cohomology is isomorphic to Fantechi and Goettsche's construction. Since our constructions do not use complex curves, stable maps, admissible covers, or moduli spaces, our results simplify the definitions of Fantechi-Goettsche's ring, of Chen-Ruan's orbifold cohomology, and of Abramovich-Graber-Vistoli's orbifold Chow. We conclude by showing that a K-theoretic version of Ruan's Hyper-Kaehler Resolution Conjecture holds for symmetric products. Our results hold both in the algebro-geometric category and in the topological category for equivariant almost complex manifolds.Comment: Exposition improved and additional details provided. To appear in Inventiones Mathematica

A/Hong Kong/483/97 (H5N1) influenza virus (HK483) isolated from the third patient during the outbreak of chicken and human influenza in Hong Kong in 1997 was shown to be neurovirulent in mice. HK483 was inoculated intranasally to mice, and the invasion routes of the virus in the central nervous system (CNS) were investigated by immunohistochemical and in situ hybridization. The pathological changes consisted of bronchopneumonia, ganglionitis, and nonpurulent encephalomyelitis of the brain stem and the anterior part of the thoracic cord. Viral antigens and viral nucleic acids (RNA and mRNA) were demonstrated in the pterygopalatine, trigeminal and superior ganglions prior to or simultaneously with their detection in the CNS. The antigens and nucleic acids were also observed in the olfactory bulb from an early stage of the infection. In the spinal cord, virus-infected cells were first demonstrated in the grey matter of the thoracic cord. The virus, which primarily replicated in the lungs, was considered to invade the thoracic cord via cardiopulmonary splanchnic nerves and sympathetic nerves. These findings indicate that the virus reached the CNS through afferent fibers of the olfactory, vagal, trigeminal, and sympathetic nerves following replication in the respiratory mucosa.

Abstract. We construct a real compactification of the moduli space of punctured rational algebraic curves and show how its geometry yields operads governing homotopy Lie algebras, gravity algebras and Batalin-Vilkovisky algebras. These algebras appeared recently in the context of string theory, and we give a simple deduction of these algebraic structures from the formal axioms of conformal field theory and string theory. The physical importance of these structures is that they lead toward the classification of string theories at the tree level, because the structure constants of the algebras appear as all correlators of the theory. We suggest that an appropriate background for putting together those algebraic structures is the structure of an operad. On the one hand, as we point out, a conformal field theory at the tree level is equivalent to an algebra over the operad of Riemann spheres with punctures, cf. Huang and Lepowsky [22]. On the other hand, this one operad gives rise to several other operads creating these various algebraic structures. The relevance to physics is that theories such as conformal field theory or string-field theory provide a representation of the geometry of the moduli space of such punctured Riemann spheres in the category of differential graded vector spaces. This paper, one of a series, deals with a part of these algebraic structures, namely with the structure of a homotopy Lie algebra and the related structures of the gravity algebra and Batalin-Vilkovisky algebra. A richer structure, the moduli space of Riemann spheres, induces a homotopy version of a Gerstenhaber algebra, which contains