21 research outputs found
Anomalous polymer collapse winding angle distributions
In two dimensions polymer collapse has been shown to be complex with multiple
low temperature states and multi-critical points. Recently, strong numerical
evidence has been provided for a long-standing prediction of universal scaling
of winding angle distributions, where simulations of interacting self-avoiding
walks show that the winding angle distribution for N-step walks is compatible
with the theoretical prediction of a Gaussian with a variance growing
asymptotically as C log N . Here we extend this work by considering interacting
self-avoiding trails which are believed to be a model representative of some of
the more complex behaviour. We provide robust evidence that, while the high
temperature swollen state of this model has a winding angle distribution that
is also Gaussian, this breaks down at the polymer collapse point and at low
temperatures. Moreover, we provide some evidence that the distributions are
well modelled by stretched/compressed exponentials, in contradistinction to the
behaviour found in interacting self-avoiding walks.Comment: 9 pages, 7 figure
Winding angle distributions for two-dimensional collapsing polymers
9 pages, 5 figures, (this version: email address corrected
Synthesis and Pharmacological Evaluation of New N-Sulfonylureas as NLRP3 Inflammasome Inhibitors: Identification of a Hit Compound to Treat Gout
NLRP3 is involved in the pathophysiology of several inflammatory diseases. Therefore, there is high current interest in the clinical development of new NLRP3 inflammasome small inhibitors to treat these diseases. Novel N-sulfonylureas were obtained by the replacement of the hexahydroindacene moiety of the previously described NLRP3 inhibitor MCC950. These new derivatives show moderate to high potency in inhibiting IL-1β release in vitro. The greatest effect was observed for compound 4b, which was similar to MCC950. Moreover, compound 4b was able to reduce caspase-1 activation, oligomerization of ASC, and therefore, IL-1β processing. Additional in silico predictions confirmed the safety profile of compound 4b, and in vitro studies in AML12 hepatic cells confirmed the absence of toxicological effects. Finally, we evaluated in vivo anti-inflammatory properties of compound 4b, which showed a significant anti-inflammatory effect and reduced mechanical hyperalgesia at 3 and 10 mg/kg (i.p.) in an in vivo mouse model of gout.J.E. thanks Fondo de Investigaciones Sanitarias (ISCIII/
FEDER) (Programa Miguel Servet: CP19/00005 and PI19/
00082) and Fundación Mutua Madrileñ a. D.D.-I. thanks the
Spanish Ministry of Science, Innovation, and Universities for
predoctoral FPU grant
Serum amyloid a1/toll-like receptor-4 Axis, an important link between inflammation and outcome of TBI patients
Traumatic brain injury (TBI) is one of the leading causes of mortality and disability world-wide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patientsThis work was supported by grants from Fundación Mutua Madrileña and Fondo de
Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet CP14/00008; CPII19/00005;
PI16/00735; PI19/00082) to JE, RYC2019-026870-I to JMR and PI18/01387 to A