11,441 research outputs found
Rational Basis Review Irrationally Applied: The Legalization of Same-Sex Marriage by the Supreme Judicial Court of Massachusetts in Goodridge v. Department of Public Health
Inferring the Rate-Length Law of Protein Folding
We investigate the rate-length scaling law of protein folding, a key
undetermined scaling law in the analytical theory of protein folding. We
demonstrate that chain length is a dominant factor determining folding times,
and that the unambiguous determination of the way chain length corre- lates
with folding times could provide key mechanistic insight into the folding
process. Four specific proposed laws (power law, exponential, and two stretched
exponentials) are tested against one an- other, and it is found that the power
law best explains the data. At the same time, the fit power law results in
rates that are very fast, nearly unreasonably so in a biological context. We
show that any of the proposed forms are viable, conclude that more data is
necessary to unequivocally infer the rate-length law, and that such data could
be obtained through a small number of protein folding experiments on large
protein domains
Intermolecular correlations are necessary to explain diffuse scattering from protein crystals
Conformational changes drive protein function, including catalysis,
allostery, and signaling. X-ray diffuse scattering from protein crystals has
frequently been cited as a probe of these correlated motions, with significant
potential to advance our understanding of biological dynamics. However, recent
work challenged this prevailing view, suggesting instead that diffuse
scattering primarily originates from rigid body motions and could therefore be
applied to improve structure determination. To investigate the nature of the
disorder giving rise to diffuse scattering, and thus the potential applications
of this signal, a diverse repertoire of disorder models was assessed for its
ability to reproduce the diffuse signal reconstructed from three protein
crystals. This comparison revealed that multiple models of intramolecular
conformational dynamics, including ensemble models inferred from the Bragg
data, could not explain the signal. Models of rigid body or short-range
liquid-like motions, in which dynamics are confined to the biological unit,
showed modest agreement with the diffuse maps, but were unable to reproduce
experimental features indicative of long-range correlations. Extending a model
of liquid-like motions to include disorder across neighboring proteins in the
crystal significantly improved agreement with all three systems and highlighted
the contribution of intermolecular correlations to the observed signal. These
findings anticipate a need to account for intermolecular disorder in order to
advance the interpretation of diffuse scattering to either extract biological
motions or aid structural inference.Comment: 12 pages, 5 figures (not including Supplementary Information
Finite domination and Novikov rings. Iterative approach
Suppose C is a bounded chain complex of finitely generated free modules over
the Laurent polynomial ring L = R[x,1/x]. Then C is R-finitely dominated, ie,
homotopy equivalent over R to a bounded chain complex of finitely generated
projective R-modules, if and only if the two chain complexes C((x)) and
C((1/x)) are acyclic, as has been proved by Ranicki. Here C((x)) is the tensor
product over L of C with the Novikov ring R((x)) = R[[x]][1/x] (also known as
the ring of formal Laurent series in x); similarly, C((1/x)) is the tensor
product over L of C with the Novikov ring R((1/x)) = R[[1/x]][x].
In this paper, we prove a generalisation of this criterion which allows us to
detect finite domination of bounded below chain complexes of projective modules
over Laurent rings in several indeterminates.Comment: 15 pages; diagrams typeset with Paul Taylor's "diagrams" macro
package. Version 2: clarified proof of main theorem, fixed minor typos;
Version 3: expanded introduction, now 16 pages; Version 4: corrected mistake
on functoriality of mapping tor
FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.
BackgroundFTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease.MethodsMice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice.ResultsAdministration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation.ConclusionThese findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model
IFN-gamma-mediated suppression of coronavirus replication in glial-committed progenitor cells.
The neurotropic JHM strain of mouse hepatitis virus (JHMV) replicates primarily within glial cells following intracranial inoculation of susceptible mice, with relative sparing of neurons. This study demonstrates that glial cells derived from neural progenitor cells are susceptible to JHMV infection and that treatment of infected cells with IFN-gamma inhibits viral replication in a dose-dependent manner. Although type I IFN production is muted in JHMV-infected glial cultures, IFN-beta is produced following IFN-gamma-treatment of JHMV-infected cells. Also, direct treatment of infected glial cultures with recombinant mouse IFN-alpha or IFN-beta inhibits viral replication. IFN-gamma-mediated control of JHMV replication is dampened in glial cultures derived from the neural progenitor cells of type I receptor knock-out mice. These data indicate that JHMV is capable of infecting glial cells generated from neural progenitor cells and that IFN-gamma-mediated control of viral replication is dependent, in part, on type I IFN secretion
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