Differential in vitro infection of neural cells by astroviruses

Encephalitis remains a diagnostic conundrum in humans as over 50% of cases are managed without the identification of an etiology. Astroviruses have been detected from the central nervous system of mammals in association with disease, suggesting that this family of RNA viruses could be responsible for cases of some neurological diseases that are currently without an ascribed etiology. However, there are significant barriers to understanding astrovirus infection as the capacity of these viruses to replicate in nervous system cells in vitro has not been determined. We describe primary and immortalized cultured cells of the nervous system that support infection by astroviruses. These results further corroborate the role of astroviruses in causing neurological diseases and will serve as an essential model to interrogate the neuropathogenesis of astrovirus infection.Recent advances in unbiased pathogen discovery have implicated astroviruses as pathogens of the central nervous system (CNS) of mammals, including humans. However, the capacity of astroviruses to be cultured in CNS-derived cells in vitro has not been reported to date. Both astrovirus VA1/HMO-C (VA1; mamastrovirus 9) and classic human astrovirus 4 (HAstV4; mamastrovirus 1) have been previously detected from cases of human encephalitis. We tested the ability of primary human neurons, primary human astrocytes, and other immortalized human nervous system cell lines (SK-N-SH, U87 MG, and SW-1088) to support infection and replication of these two astrovirus genotypes. Primary astrocytes and SK-N-SH cells supported the full viral life cycle of VA1 with a >100-fold increase in viral RNA levels during a multistep growth curve, detection of viral capsid, and a >100-fold increase in viral titer. Primary astrocytes were permissive with respect to HAstV4 infection and replication but did not yield infectious virus, suggesting abortive infection. Similarly, abortive infection of VA1 was observed in SW-1088 and U87 MG cells. Elevated expression of the chemokine CXCL10 was detected in VA1-infected primary astrocytes and SK-N-SH cells, suggesting that VA1 infection can induce a proinflammatory host response. These findings establish an in vitro cell culture model that is essential for investigation of the basic biology of astroviruses and their neuropathogenic potential

Algebraic Aspects of Abelian Sandpile Models

The abelian sandpile models feature a finite abelian group G generated by the operators corresponding to particle addition at various sites. We study the canonical decomposition of G as a product of cyclic groups G = Z_{d_1} X Z_{d_2} X Z_{d_3}...X Z_{d_g}, where g is the least number of generators of G, and d_i is a multiple of d_{i+1}. The structure of G is determined in terms of toppling matrix. We construct scalar functions, linear in height variables of the pile, that are invariant toppling at any site. These invariants provide convenient coordinates to label the recurrent configurations of the sandpile. For an L X L square lattice, we show that g = L. In this case, we observe that the system has nontrivial symmetries coming from the action of the cyclotomic Galois group of the (2L+2)th roots of unity which operates on the set of eigenvalues of the toppling matrix. These eigenvalues are algebraic integers, whose product is the order |G|. With the help of this Galois group, we obtain an explicit factorizaration of |G|. We also use it to define other simpler, though under-complete, sets of toppling invariants.Comment: 39 pages, TIFR/TH/94-3

Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix.

The refinement of biomolecular crystallographic models relies on geometric restraints to help to address the paucity of experimental data typical in these experiments. Limitations in these restraints can degrade the quality of the resulting atomic models. Here, an integration of the full all-atom Amber molecular-dynamics force field into Phenix crystallographic refinement is presented, which enables more complete modeling of biomolecular chemistry. The advantages of the force field include a carefully derived set of torsion-angle potentials, an extensive and flexible set of atom types, Lennard-Jones treatment of nonbonded interactions and a full treatment of crystalline electrostatics. The new combined method was tested against conventional geometry restraints for over 22 000 protein structures. Structures refined with the new method show substantially improved model quality. On average, Ramachandran and rotamer scores are somewhat better, clashscores and MolProbity scores are significantly improved, and the modeling of electrostatics leads to structures that exhibit more, and more correct, hydrogen bonds than those refined using traditional geometry restraints. In general it is found that model improvements are greatest at lower resolutions, prompting plans to add the Amber target function to real-space refinement for use in electron cryo-microscopy. This work opens the door to the future development of more advanced applications such as Amber-based ensemble refinement, quantum-mechanical representation of active sites and improved geometric restraints for simulated annealing

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

Periodic One-Dimensional Hopping Model with one Mobile Directional Impurity

Analytic solution is given in the steady state limit for the system of Master equations describing a random walk on one-dimensional periodic lattices with arbitrary hopping rates containing one mobile, directional impurity (defect bond). Due to the defect, translational invariance is broken, even if all other rates are identical. The structure of Master equations lead naturally to the introduction of a new entity, associated with the walker-impurity pair which we call the quasi-walker. The velocities and diffusion constants for both the random walker and impurity are given, being simply related to that of the quasi-particle through physically meaningful equations. Applications in driven diffusive systems are shown, and connections with the Duke-Rubinstein reptation models for gel electrophoresis are discussed.Comment: 31 LaTex pages, 5 Postscript figures included, to appear in Journal of Statistical Physic

Motion of a driven tracer particle in a one-dimensional symmetric lattice gas

We study the dynamics of a tracer particle subject to a constant driving force $E$ in a one-dimensional lattice gas of hard-core particles whose transition rates are symmetric. We show that the mean displacement of the driven tracer grows in time, $t$, as $\sqrt{\alpha t}$, rather than the linear time dependence found for driven diffusion in the bath of non-interacting (ghost) particles. The prefactor $\alpha$ is determined implicitly, as the solution of a transcendental equation, for an arbitrary magnitude of the driving force and an arbitrary concentration of the lattice gas particles. In limiting cases the prefactor is obtained explicitly. Analytical predictions are seen to be in a good agreement with the results of numerical simulations.Comment: 21 pages, LaTeX, 4 Postscript fugures, to be published in Phys. Rev. E, (01Sep, 1996

Domain wall QCD with physical quark masses

We present results for several light hadronic quantities ($f_\pi$, $f_K$, $B_K$, $m_{ud}$, $m_s$, $t_0^{1/2}$, $w_0$) obtained from simulations of 2+1 flavor domain wall lattice QCD with large physical volumes and nearly-physical pion masses at two lattice spacings. We perform a short, O(3)%, extrapolation in pion mass to the physical values by combining our new data in a simultaneous chiral/continuum `global fit' with a number of other ensembles with heavier pion masses. We use the physical values of $m_\pi$, $m_K$ and $m_\Omega$ to determine the two quark masses and the scale - all other quantities are outputs from our simulations. We obtain results with sub-percent statistical errors and negligible chiral and finite-volume systematics for these light hadronic quantities, including: $f_\pi$ = 130.2(9) MeV; $f_K$ = 155.5(8) MeV; the average up/down quark mass and strange quark mass in the $\bar {\rm MS}$ scheme at 3 GeV, 2.997(49) and 81.64(1.17) MeV respectively; and the neutral kaon mixing parameter, $B_K$, in the RGI scheme, 0.750(15) and the $\bar{\rm MS}$ scheme at 3 GeV, 0.530(11).Comment: 131 pages, 30 figures. Updated to match published versio

Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats

Peer reviewedPublisher PD