558 research outputs found
Influence of the Environment Fluctuations on Incoherent Neutron Scattering Functions
In extending the conventional dynamic models, we consider a simple model to
account for the environment fluctuations of particle atoms in a protein system
and derive the elastic incoherent structure factor (EISF) and the incoherent
scattering correlation function C(Q,t) for both the jump dynamics between sites
with fluctuating site interspacing and for the diffusion inside a fluctuating
sphere. We find that the EISF of the system (or the normalized elastic
intensity) is equal to that in the absence of fluctuations averaged over the
distribution of site interspacing or sphere radius a. The scattering
correlation function is ,
where the average is taken over the Q-dependent effective distribution of
relaxation rates \lambda_n(a) and \psi(t) is the correlation function of the
length a. When \psi(t)=1, the relaxation of C(Q,t) is exponential for the jump
dynamics between sites (since \lambda_n(a) is independent of a) while it is
nonexponential for diffusion inside a sphere.Comment: 7 pages, 7 eps figure
Crystal-like high frequency phonons in the amorphous phases of solid water
The high frequency dynamics of low- (LDA) and high-density amorphous-ice
(HDA) and of cubic ice (I_c) has been measured by inelastic X-ray Scattering
(IXS) in the 1-15 nm^{-1} momentum transfer (Q) range. Sharp phonon-like
excitations are observed, and the longitudinal acoustic branch is identified up
to Q = 8nm^{-1} in LDA and I_c and up to 5nm^{-1} in HDA. The narrow width of
these excitations is in sharp contrast with the broad features observed in all
amorphous systems studied so far. The "crystal-like" behavior of amorphous
ices, therefore, implies a considerable reduction in the number of decay
channels available to sound-like excitations which is assimilated to low local
disorder.Comment: 4 pages, 3 figure
A versatile protocol for StilleâMigita cross coupling reactions
The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent StilleâMigita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact
Spectral Signatures of the Diffusional Anomaly in Water
Analysis of power spectrum profiles for various tagged particle quantities in
bulk SPC/E water is used to demonstrate that variations in mobility associated
with the diffusional anomaly are mirrored in the exponent of the \onebyf\
region. Monitoring of \onebyf behaviour is shown to be a simple and direct
method for linking phenomena on three distinctive length and time scales: the
local molecular environment, hydrogen bond network reorganisations and the
diffusivity. The results indicate that experimental studies of supercooled
water to probe the density dependence of spectral features, or
equivalent stretched exponential behaviour in time-correlation functions, will
be of interest.Comment: 5 Pages, 4 Figure
Liquid Polymorphism and Double Criticality in a Lattice Gas Model
We analyze the possible phase diagrams of a simple model for an associating
liquid proposed previously. Our two-dimensional lattice model combines
oreintati onal ice-like interactions and \"{}Van der Waals\"{} interactions
which may be repulsive, and in this case represent a penalty for distortion of
hydrogen bonds in the presence of extra molecules. These interactions can be
interpreted in terms of two competing distances, but not necessarily soft-core.
We present mean -field calculations and an exhaustive simulation study for
different parameters which represent relative strength of the bonding
interaction to the energy penalty for its distortion. As this ratio decreases,
a smooth disappearance of the doubl e criticality occurs. Possible connections
to liquid-liquid transitions of molecul ar liquids are suggested
Liquid-Liquid Phase Transition for an Attractive Isotropic Potential with Wide Repulsive Range
Recent experimental and theoretical results have shown the existence of a
liquid-liquid phase transition in isotropic systems, such as biological
solutions and colloids, whose interaction can be represented via an effective
potential with a repulsive soft-core and an attractive part. We investigate how
the phase diagram of a schematic general isotropic system, interacting via a
soft-core squared attractive potential, changes by varying the parameters of
the potential. It has been shown that this potential has a phase diagram with a
liquid-liquid phase transition in addition to the standard gas-liquid phase
transition and that, for a short-range soft-core, the phase diagram resulting
from molecular dynamics simulations can be interpreted through a modified van
der Waals equation. Here we consider the case of soft-core ranges comparable
with or larger than the hard-core diameter. Because an analysis using molecular
dynamics simulations of such systems or potentials is too time-demanding, we
adopt an integral equation approach in the hypernetted-chain approximation.
Thus we can estimate how the temperature and density of both critical points
depend on the potential's parameters for large soft-core ranges. The present
results confirm and extend our previous analysis, showing that this potential
has two fluid-fluid critical points that are well separated in temperature and
in density only if there is a balance between the attractive and repulsive part
of the potential. We find that for large soft-core ranges our results satisfy a
simple relation between the potential's parameters
Static and dynamic evaluation of pelvic floor disorders with an open low-field tilting magnet.
AIM:
To assess the feasibility of magnetic resonance defaecography (MRD) in pelvic floor disorders using an open tilting magnet with a 0.25 T static field and to compare the results obtained from the same patient both in supine and orthostatic positions.
MATERIALS AND METHODS:
From May 2010 to November 2011, 49 symptomatic female subjects (mean age 43.5 years) were enrolled. All the patients underwent MRD in the supine and orthostatic positions using three-dimensional (3D) hybrid contrast-enhanced (HYCE) sequences and dynamic gradient echo (GE) T1-weighted sequences. All the patients underwent conventional defaecography (CD) to correlate both results. Two radiologists evaluated the examinations; inter and intra-observer concordance was measured. The results obtained in the two positions were compared between them and with CD.
RESULTS:
The comparison between CD and MRD found statistically significant differences in the evaluation of anterior and posterior rectocoele during defaecation in both positions and of rectal prolapse under the pubo-coccygeal line (PCL) during evacuation, only in the supine position (versus MRD orthostatic: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.008; versus CD: rectal prolapse p < 0.0001; anterior rectocoele p < 0.001; posterior rectocoele p = 0.01). The value of intra-observer intra-class correlation coefficient (ICC) ranged from good to excellent; the interobserver ICC from moderate to excellent.
CONCLUSION:
MRD is feasible with an open low-field tilting magnet, and it is more accurate in the orthostatic position than in the supine position to evaluate pelvic floor disorders
GLUT1 and LOX inhibitors as perspective anticancer agents tackling glucose avidity and ECM remodeling in tumors
Introduction
Most cancers have large hypoxic regions, which display an increase of the glycolytic metabolism leading to the production of lactate, providing cancer cells with adequate amounts of energy and anabolites. To this end, tumor cells generally overexpress glucose transporters (GLUTs), in particular GLUT1, which results in an increased uptake of glucose to support their less efficient energy production (Warburg effect). Therefore, therapeutic interventions aimed at reducing cancer glycolysis may be implemented by several strategies, including the development of inhibitors of glucose transporters. Furthermore, extracellular matrix (ECM) remodeling is one of the key processes preluding metastatic invasion, and it is promoted by several effectors, such as lysyl oxidase (LOX), an enzyme commonly involved in extracellular matrix maturation. LOX is up-regulated by HIF-1 and plays a critical role in the development of metastasis. Therefore, LOX inhibitors may represent an additional and innovative strategy for the treatment and the prevention of metastatic cancer.
Methods
We have developed various classes of compounds that are able to interfere with GLUTs (Granchi et al. 2015, Tuccinardi et al. 2013) and LOX (Granchi et al. 2009) by molecular design and chemical synthesis. Their effect on cell proliferation, apoptosis, migration and other key determinants of activity were evaluated by sulforhodamine-B and luciferase assays, FACS, wound-healing assay, and Quantitative PCR. The studies were performed in seven PDAC cells, including five primary-cell-cultures and 3D co-cultures with human stellate cells, in normoxic and hypoxic conditions.
Results
The IC50s of the tested compounds ranged from 13.9 to 32.0 ÎŒM after 72-hour exposure. Notably, these compounds were still active in 3D co-cultures of these tumor cells with pancreatic stellate cells, which showed increased resistance to gemcitabine and are more representative of the dense stromal compartment with core hypoxic areas of this tumor type, as detected by immunohistochemical stainings. Remarkably, one compound (PGL-14) showed a synergistic interaction with gemcitabine, increasing apoptosis induction and accumulation of ROS. Furthermore, the combination of these drugs reduced cell migration and enhanced in vitro sensitivity to anoikis, suggesting the ability of these compounds to inhibit metastasis.
Discussion
GLUT1 inhibitors were more active in hypoxia, but still active also in normoxia. Conversely, we did not detect cytotoxic effects using the LOX-inhibitors in normoxia (at concentration until 50 ÎŒM) since they were designed as bioreductively activated prodrugs, which are therefore activated only under hypoxic conditions. However, at O2 tension of 1%, IC50s were below 10 ÎŒM. As reported previously, LOX inhibition was associated with reduction of the mRNA levels of fibronectin, suggesting that it might also have impact on the interaction of tumor cells with the stroma that are mediated by integrins and fibronectin, regulating tissue stiffness (Coppola et al. 2017).
Conclusion
Interventions aimed at blocking the glycolytic activity or the extracellular matrix remodeling of tumors by means of newly designed molecules proved to exert a synergistic effect with clinically approved drugs, such as gemcitabine. These results seem to support the strategy of the simultaneous GLUT/LOX-inhibition in order to further sensitize hypoxic cancer portions to chemotherapy.
Bibliography
C. Granchi, et al. ChemMedChem 2009, 4, 1590-1594. C. Granchi, et al. ChemMedChem 2015, 10, 1892-1900. T. Tuccinardi, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923-6927. Coppola S, et al. Drug Resist Updat. 2017, 31, 43-51
Dynamically Slow Processes in Supercooled Water Confined Between Hydrophobic Plates
We study the dynamics of water confined between hydrophobic flat surfaces at
low temperature. At different pressures, we observe different behaviors that we
understand in terms of the hydrogen bonds dynamics. At high pressure, the
formation of the open structure of the hydrogen bond network is inhibited and
the surfaces can be rapidly dehydrated by decreasing the temperature. At lower
pressure the rapid ordering of the hydrogen bonds generates heterogeneities
that are responsible for strong non-exponential behavior of the correlation
function, but with no strong increase of the correlation time. At very low
pressures, the gradual formation of the hydrogen bond network is responsible
for the large increase of the correlation time and, eventually, the dynamical
arrest of the system and of the dehydration process.Comment: 14 pages, 3 figure
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