3,120 research outputs found
Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins
Protein aggregation, linked to many of diseases, is initiated when monomers
access rogue conformations that are poised to form amyloid fibrils. We show,
using simulations of src SH3 domain, that mechanical force enhances the
population of the aggregation prone () states, which are rarely populated
under force free native conditions, but are encoded in the spectrum of native
fluctuations. The folding phase diagrams of SH3 as a function of denaturant
concentration (), mechanical force (), and temperature exhibit an
apparent two-state behavior, without revealing the presence of the elusive
states. Interestingly, the phase boundaries separating the folded and
unfolded states at all [C] and fall on a master curve, which can can be
quantitatively described using an analogy to superconductors in a magnetic
field. The free energy profiles as a function of the molecular extension (),
which are accessible in pulling experiments, (), reveal the presence of a
native-like with a disordered solvent-exposed amino terminal
-strand. The structure of the state is identical to that found in
Fyn SH3 by NMR dispersion experiments. We show that the time scale for fibril
formation can be estimated from the population of the state, determined
by the free energy gap separating the native structure and the state, a
finding that can be used to assess fibril forming tendencies of proteins. The
structures of the state are used to show that oligomer formation and
likely route to fibrils occur by a domain-swap mechanism in SH3 domain.Comment: 12 pages, 8 figures, 9 supplementary figures (on 5 more pages), 2
supplementary movies (on youtube
Timed and targeted differential regulation of nitric oxide synthase (NOS) and anti-NOS genes by reward conditioning leading to long-term memory formation
In a number of neuronal models of learning, signaling by the neurotransmitter nitric oxide (NO), synthesized by the enzyme neuronal NO synthase (nNOS), is essential for the formation of long-term memory (LTM). Using the molluscan model system Lymnaea, we investigate here whether LTM formation is associated with specific changes in the activity of members of the NOS gene family: Lym-nNOS1, Lym-nNOS2, and the antisense RNA-producing pseudogene (anti-NOS). We show that expression of the Lym-nNOS1 gene is transiently upregulated in cerebral ganglia after conditioning. The activation of the gene is precisely timed and occurs at the end of a critical period during which NO is required for memory consolidation. Moreover, we demonstrate that this induction of the Lym-nNOS1 gene is targeted to an identified modulatory neuron called the cerebral giant cell (CGC). This neuron gates the conditioned feeding response and is an essential part of the neural network involved in LTM formation. We also show that the expression of the anti-NOS gene, which functions as a negative regulator of nNOS expression, is downregulated in the CGC by training at 4 h after conditioning, during the critical period of NO requirement. This appears to be the first report of the timed and targeted differential regulation of the activity of a group of related genes involved in the production of a neurotransmitter that is necessary for learning, measured in an identified neuron of known function. We also provide the first example of the behavioral regulation of a pseudogene
Suppression of nitric oxide (NO)-dependent behavior by double-stranded RNA-mediated silencing of a neuronal NO synthase gene
We have used double-stranded RNA (dsRNA)-mediated RNA interference (RNAi) to disrupt neuronal nitric oxide (NO) synthase (nNOS) gene function in the snail Lymnaea stagnalis and have detected a specific behavioral phenotype. The injection of whole animals with synthetic dsRNA molecules targeted to the nNOS-encoding mRNA reduces feeding behavior in vivo and fictive feeding in vitro and interferes with NO synthesis by the CNS. By showing that synthetic dsRNA targeted to the nNOS mRNA causes a significant and long-lasting reduction in the levels of Lym-nNOS mRNA, we verify that specific RNAi has occurred. Importantly, our results establish that the expression of nNOS gene is essential for normal feeding behavior. They also show that dsRNA can be used in the investigation of functional gene expression in the context of whole animal behavior, regardless of the availability of targeted mutation technologies
KDEL-cargo regulates interactions between proteins involved in COPI vesicle traffic: Measurements in living cells using FRET
Anti-phospholipid-antibodies in patients with relapsing polychondritis
Relapsing polychondritis (RP) is an extremly rare multisystemic disease thought to be of autoimmune origin. In order to assess if RP is associated with anti-phospholipid antibodies (aPL), clinical data and sera of 21 patients with RP were collected in a multicentre study. Concentration of anti-cardiolipin antibodies (aCL) (IgG-, IgM-and IgA-isotypes), anti-phosphatidylserine-antibodies (aPS) (IgG-and IgM-isotypes) and anti-β-2-glycoprotein I-antibodies (aβ2 GPI) were measured by ELISA. In eight patients aCL were found to be elevated. One patient had elevated aPS. No patient had elevated aβ2 GPI. No patient had clinical signs and symptoms of a aPL syndrome. Interestingly, the two RP patients with the highest aPL had concomitant systemic lupus erythematosus (SLE). Therefore the presence of elevated aPL in RP is probably more closely related to an associated SLE than to RP itself. There is no convincing evidence that aPL are associated with RP
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Winter 1973
Field Evaluation of Insecticides for Controlling Mole Crickets in Turf (page 3) Calculations for Turfgrass Culture II: Pesticides (6) Progress in the Control of Turfgrass Weevil, a Species of Hyperodes (9) A Look at USDA\u27s Biological Control of Insect Pests: 1888 to Present (14) Turf Bulletin Index 1970-1973 (23
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