883 research outputs found
Prediction of anti-Alzheimer’s activity of flavonoids targeting acetylcholinesterase in silico
Introduction – Prenylated and pyrano-flavonoids of the genus Artocarpus J. R. Forster & G. Forster are well known for their acetylcholinesterase (AchE) inhibitory, anticholinergic, antiinflammatory, antimicrobial, antioxidant, antiproliferative and tyrosinase inhibitory activities. Some of these compounds have also been shown to be effective against Alzheimer’s disease. Objective – The aim of the in silico study was to establish protocols to predict the most effective flavonoid from prenylated and pyrano-flavonoid classes for AchE inhibition linking to the potential treatment of Alzheimer’s disease. Methodology – Three flavonoids isolated from Artocarpus anisophyllus Miq. were selected for the study. With these compounds, Lipinski filter, ADME/Tox screening, molecular docking and QSAR were performed in silico. In vitro activity was evaluated by bioactivity staining based on the Ellman’s method. Results – In the Lipinski filter and ADME/Tox screening, all test compounds produced positive results, but in the target fishing, only one flavonoid could successfully target AchE. Molecular docking was performed on this flavonoid, and this compound gained the score as -13.5762. From the QSAR analysis the IC50 was found to be 1659.59 nM. Again, 100 derivatives were generated from the parent compound and docking was performed. The derivative number 20 was the best scorer i.e., -31.6392 and IC50 was predicted as 6.025 nM. Conclusion – Results indicated that flavonoids could be efficient inhibitors of AchE and thus, could be useful in the management of Alzheimer’s disease
Portfolio selection problems in practice: a comparison between linear and quadratic optimization models
Several portfolio selection models take into account practical limitations on
the number of assets to include and on their weights in the portfolio. We
present here a study of the Limited Asset Markowitz (LAM), of the Limited Asset
Mean Absolute Deviation (LAMAD) and of the Limited Asset Conditional
Value-at-Risk (LACVaR) models, where the assets are limited with the
introduction of quantity and cardinality constraints. We propose a completely
new approach for solving the LAM model, based on reformulation as a Standard
Quadratic Program and on some recent theoretical results. With this approach we
obtain optimal solutions both for some well-known financial data sets used by
several other authors, and for some unsolved large size portfolio problems. We
also test our method on five new data sets involving real-world capital market
indices from major stock markets. Our computational experience shows that,
rather unexpectedly, it is easier to solve the quadratic LAM model with our
algorithm, than to solve the linear LACVaR and LAMAD models with CPLEX, one of
the best commercial codes for mixed integer linear programming (MILP) problems.
Finally, on the new data sets we have also compared, using out-of-sample
analysis, the performance of the portfolios obtained by the Limited Asset
models with the performance provided by the unconstrained models and with that
of the official capital market indices
Entropic Tension in Crowded Membranes
Unlike their model membrane counterparts, biological membranes are richly
decorated with a heterogeneous assembly of membrane proteins. These proteins
are so tightly packed that their excluded area interactions can alter the free
energy landscape controlling the conformational transitions suffered by such
proteins. For membrane channels, this effect can alter the critical membrane
tension at which they undergo a transition from a closed to an open state, and
therefore influence protein function \emph{in vivo}. Despite their obvious
importance, crowding phenomena in membranes are much less well studied than in
the cytoplasm.
Using statistical mechanics results for hard disk liquids, we show that
crowding induces an entropic tension in the membrane, which influences
transitions that alter the projected area and circumference of a membrane
protein. As a specific case study in this effect, we consider the impact of
crowding on the gating properties of bacterial mechanosensitive membrane
channels, which are thought to confer osmoprotection when these cells are
subjected to osmotic shock. We find that crowding can alter the gating energies
by more than in physiological conditions, a substantial fraction of
the total gating energies in some cases.
Given the ubiquity of membrane crowding, the nonspecific nature of excluded
volume interactions, and the fact that the function of many membrane proteins
involve significant conformational changes, this specific case study highlights
a general aspect in the function of membrane proteins.Comment: 20 pages (inclduing supporting information), 4 figures, to appear in
PLoS Comp. Bio
Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts
Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia.
Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased.
Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia
Magnetism, FeS colloids, and Origins of Life
A number of features of living systems: reversible interactions and weak
bonds underlying motor-dynamics; gel-sol transitions; cellular connected
fractal organization; asymmetry in interactions and organization; quantum
coherent phenomena; to name some, can have a natural accounting via
interactions, which we therefore seek to incorporate by expanding the horizons
of `chemistry-only' approaches to the origins of life. It is suggested that the
magnetic 'face' of the minerals from the inorganic world, recognized to have
played a pivotal role in initiating Life, may throw light on some of these
issues. A magnetic environment in the form of rocks in the Hadean Ocean could
have enabled the accretion and therefore an ordered confinement of
super-paramagnetic colloids within a structured phase. A moderate H-field can
help magnetic nano-particles to not only overcome thermal fluctuations but also
harness them. Such controlled dynamics brings in the possibility of accessing
quantum effects, which together with frustrations in magnetic ordering and
hysteresis (a natural mechanism for a primitive memory) could throw light on
the birth of biological information which, as Abel argues, requires a
combination of order and complexity. This scenario gains strength from
observations of scale-free framboidal forms of the greigite mineral, with a
magnetic basis of assembly. And greigite's metabolic potential plays a key role
in the mound scenario of Russell and coworkers-an expansion of which is
suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed
Krishnaswami Alladi, Springer 201
Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype
Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions
Scalar and vector Slepian functions, spherical signal estimation and spectral analysis
It is a well-known fact that mathematical functions that are timelimited (or
spacelimited) cannot be simultaneously bandlimited (in frequency). Yet the
finite precision of measurement and computation unavoidably bandlimits our
observation and modeling scientific data, and we often only have access to, or
are only interested in, a study area that is temporally or spatially bounded.
In the geosciences we may be interested in spectrally modeling a time series
defined only on a certain interval, or we may want to characterize a specific
geographical area observed using an effectively bandlimited measurement device.
It is clear that analyzing and representing scientific data of this kind will
be facilitated if a basis of functions can be found that are "spatiospectrally"
concentrated, i.e. "localized" in both domains at the same time. Here, we give
a theoretical overview of one particular approach to this "concentration"
problem, as originally proposed for time series by Slepian and coworkers, in
the 1960s. We show how this framework leads to practical algorithms and
statistically performant methods for the analysis of signals and their power
spectra in one and two dimensions, and, particularly for applications in the
geosciences, for scalar and vectorial signals defined on the surface of a unit
sphere.Comment: Submitted to the 2nd Edition of the Handbook of Geomathematics,
edited by Willi Freeden, Zuhair M. Nashed and Thomas Sonar, and to be
published by Springer Verlag. This is a slightly modified but expanded
version of the paper arxiv:0909.5368 that appeared in the 1st Edition of the
Handbook, when it was called: Slepian functions and their use in signal
estimation and spectral analysi
Power analysis for genome-wide association studies
Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.</p
Bioinformatics in crosslinking chemistry of collagen with selective cross linkers
<p>Abstract</p> <p>Background</p> <p>Identifying the molecular interactions using bioinformatics tools before venturing into wet lab studies saves the energy and time considerably. The present study summarizes, molecular interactions and binding energy calculations made for major structural protein, collagen of Type I and Type III with the chosen cross-linkers, namely, coenzyme Q<sub>10</sub>, dopaquinone, embelin, embelin complex-1 & 2, idebenone, 5-O-methyl embelin, potassium embelate and vilangin.</p> <p>Results</p> <p>Molecular descriptive analyses suggest, dopaquinone, embelin, idebenone, 5-O-methyl embelin, and potassium embelate display nil violations. And results of docking analyses revealed, best affinity for Type I (- 4.74 kcal/mol) and type III (-4.94 kcal/mol) collagen was with dopaquinone.</p> <p>Conclusions</p> <p>Among the selected cross-linkers, dopaquinone, embelin, potassium embelate and 5-O-methyl embelin were the suitable cross-linkers for both Type I and Type III collagen and stabilizes the collagen at the expected level.</p
Regeneration limit of classical Shannon capacity
Since Shannon derived the seminal formula for the capacity of the additive linear white Gaussian noise channel, it has commonly been interpreted as the ultimate limit of error-free information transmission rate. However, the capacity above the corresponding linear channel limit can be achieved when noise is suppressed using nonlinear elements; that is, the regenerative function not available in linear systems. Regeneration is a fundamental concept that extends from biology to optical communications. All-optical regeneration of coherent signal has attracted particular attention. Surprisingly, the quantitative impact of regeneration on the Shannon capacity has remained unstudied. Here we propose a new method of designing regenerative transmission systems with capacity that is higher than the corresponding linear channel, and illustrate it by proposing application of the Fourier transform for efficient regeneration of multilevel multidimensional signals. The regenerative Shannon limit -the upper bound of regeneration efficiency -is derived
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