552 research outputs found
Histamine beyond its effects on allergy: Potential therapeutic benefits for the treatment of Amyotrophic Lateral Sclerosis (ALS)
ALS currently remains a challenge despite many efforts in performing successful clinical trials and formulating therapeutic solutions. By learning from current failures and striving for success, scientists and clinicians are checking every possibility to search for missing hints and efficacious treatments. Because the disease is very complex and heterogeneous and, moreover, targeting not only motor neurons but also several different cell types including muscle, glial, and immune cells, the right answer to ALS is conceivably a multidrug strategy or the use of broad-spectrum molecules. The aim of the present work is to gather evidence about novel perspectives on ALS pathogenesis and to present recent and innovative paradigms for therapy. In particular, we describe how an old molecule possessing immunomodulatory and neuroprotective functions beyond its recognized effects on allergy, histamine, might have a renewed and far-reaching momentum in ALS
Clypeogethes elongatus (Rosenhauer, 1856) in Sardinia (Coleoptera. Nitidulidae, Meligethinae)
Clypeogethes elongatus (Rosenhauer, 1856) is a pollen-beetle occurring in SW Mediterranean areas, from Southern Iberian Peninsula to most of the North Africa; in Italy, this uncommon species was thus far known only from the Island of Pantelleria (southern Sicily). Recent researches in S Sardinia allowed to find a small relic population of this species in Cagliari (San Michele hill), where it is cer-tainly associated with early-flowering Brassicaceae, on chalk-based rocks
Urine-Derived Stem Cells Express 571 Neuromuscular Disorders Causing Genes, Making Them a Potential in vitro Model for Rare Genetic Diseases
Background: Neuromuscular disorders (NMDs) are a heterogeneous group of genetic diseases, caused by mutations in genes involved in spinal cord, peripheral nerve, neuromuscular junction, and muscle functions. To advance the knowledge of the pathological mechanisms underlying NMDs and to eventually identify new potential drugs paving the way for personalized medicine, limitations regarding the availability of neuromuscular disease-related biological samples, rarely accessible from patients, are a major challenge. Aim: We characterized urinary stem cells (USCs) by in-depth transcriptome and protein profiling to evaluate whether this easily accessible source of patient-derived cells is suitable to study neuromuscular genetic diseases, focusing especially on those currently involved in clinical trials. Methods: The global transcriptomics of either native or MyoD transformed USCs obtained from control individuals was performed by RNA-seq. The expression of 610 genes belonging to 16 groups of disorders (http://www.musclegenetable.fr/) whose mutations cause neuromuscular diseases, was investigated on the RNA-seq output. In addition, protein expression of 11 genes related to NMDs including COL6A, EMD, LMNA, SMN, UBA1, DYNC1H1, SOD1, C9orf72, DYSF, DAG1, and HTT was analyzed in native USCs by immunofluorescence and/or Western blot (WB). Results: RNA-seq profile of control USCs shows that 571 out of 610 genes known to be involved in NMDs, are expressed in USCs. Interestingly, the expression levels of the majority of NMD genes remain unmodified following USCs MyoD transformation. Most genes involved in the pathogenesis of all 16 groups of NMDs are well represented except for channelopathies and malignant hyperthermia related genes. All tested proteins showed high expression values, suggesting consistency between transcription and protein representation in USCs. Conclusion: Our data suggest that USCs are human cells, obtainable by non-invasive means, which might be used as a patient-specific cell model to study neuromuscular disease-causing genes and that they can be likely adopted for a variety of in vitro functional studies such as mutation characterization, pathway identification, and drug screening
Point process model of 1/f noise versus a sum of Lorentzians
We present a simple point process model of noise, covering
different values of the exponent . The signal of the model consists of
pulses or events. The interpulse, interevent, interarrival, recurrence or
waiting times of the signal are described by the general Langevin equation with
the multiplicative noise and stochastically diffuse in some interval resulting
in the power-law distribution. Our model is free from the requirement of a wide
distribution of relaxation times and from the power-law forms of the pulses. It
contains only one relaxation rate and yields spectra in a wide
range of frequency. We obtain explicit expressions for the power spectra and
present numerical illustrations of the model. Further we analyze the relation
of the point process model of noise with the Bernamont-Surdin-McWhorter
model, representing the signals as a sum of the uncorrelated components. We
show that the point process model is complementary to the model based on the
sum of signals with a wide-range distribution of the relaxation times. In
contrast to the Gaussian distribution of the signal intensity of the sum of the
uncorrelated components, the point process exhibits asymptotically a power-law
distribution of the signal intensity. The developed multiplicative point
process model of noise may be used for modeling and analysis of
stochastic processes in different systems with the power-law distribution of
the intensity of pulsing signals.Comment: 23 pages, 10 figures, to be published in Phys. Rev.
Random Walks on Stochastic Temporal Networks
In the study of dynamical processes on networks, there has been intense focus
on network structure -- i.e., the arrangement of edges and their associated
weights -- but the effects of the temporal patterns of edges remains poorly
understood. In this chapter, we develop a mathematical framework for random
walks on temporal networks using an approach that provides a compromise between
abstract but unrealistic models and data-driven but non-mathematical
approaches. To do this, we introduce a stochastic model for temporal networks
in which we summarize the temporal and structural organization of a system
using a matrix of waiting-time distributions. We show that random walks on
stochastic temporal networks can be described exactly by an
integro-differential master equation and derive an analytical expression for
its asymptotic steady state. We also discuss how our work might be useful to
help build centrality measures for temporal networks.Comment: Chapter in Temporal Networks (Petter Holme and Jari Saramaki
editors). Springer. Berlin, Heidelberg 2013. The book chapter contains minor
corrections and modifications. This chapter is based on arXiv:1112.3324,
which contains additional calculations and numerical simulation
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10–7 and 1.16 x 10–6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors
Common Scaling Patterns in Intertrade Times of U. S. Stocks
We analyze the sequence of time intervals between consecutive stock trades of
thirty companies representing eight sectors of the U. S. economy over a period
of four years. For all companies we find that: (i) the probability density
function of intertrade times may be fit by a Weibull distribution; (ii) when
appropriately rescaled the probability densities of all companies collapse onto
a single curve implying a universal functional form; (iii) the intertrade times
exhibit power-law correlated behavior within a trading day and a consistently
greater degree of correlation over larger time scales, in agreement with the
correlation behavior of the absolute price returns for the corresponding
company, and (iv) the magnitude series of intertrade time increments is
characterized by long-range power-law correlations suggesting the presence of
nonlinear features in the trading dynamics, while the sign series is
anti-correlated at small scales. Our results suggest that independent of
industry sector, market capitalization and average level of trading activity,
the series of intertrade times exhibit possibly universal scaling patterns,
which may relate to a common mechanism underlying the trading dynamics of
diverse companies. Further, our observation of long-range power-law
correlations and a parallel with the crossover in the scaling of absolute price
returns for each individual stock, support the hypothesis that the dynamics of
transaction times may play a role in the process of price formation.Comment: 8 pages, 5 figures. Presented at The Second Nikkei Econophysics
Workshop, Tokyo, 11-14 Nov. 2002. A subset appears in "The Application of
Econophysics: Proceedings of the Second Nikkei Econophysics Symposium",
editor H. Takayasu (Springer-Verlag, Tokyo, 2003) pp.51-57. Submitted to
Phys. Rev. E on 25 June 200
Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice
Hutchinson\u2013Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders
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