181 research outputs found
Mesoscopic models for DNA stretching under force: new results and comparison to experiments
Single molecule experiments on B-DNA stretching have revealed one or two
structural transitions, when increasing the external force. They are
characterized by a sudden increase of DNA contour length and a decrease of the
bending rigidity. It has been proposed that the first transition, at forces of
60--80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA,
while the second one, at stronger forces, is a strand peeling resulting in
single stranded DNAs (ssDNA), similar to thermal denaturation. But due to
experimental conditions these two transitions can overlap, for instance for
poly(dA-dT). We derive analytical formula using a coupled discrete worm like
chain-Ising model. Our model takes into account bending rigidity, discreteness
of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit
of zero force, this model simplifies into a coupled model already developed by
us for studying thermal DNA melting, establishing a connexion with previous
fitting parameter values for denaturation profiles. We find that: (i) ssDNA is
fitted, using an analytical formula, over a nanoNewton range with only three
free parameters, the contour length, the bending modulus and the monomer size;
(ii) a surprisingly good fit on this force range is possible only by choosing a
monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase
length; (iii) mesoscopic models are not able to fit B to ssDNA (or S to ss)
transitions; (iv) an analytical formula for fitting B to S transitions is
derived in the strong force approximation and for long DNAs, which is in
excellent agreement with exact transfer matrix calculations; (v) this formula
fits perfectly well poly(dG-dC) and -DNA force-extension curves with
consistent parameter values; (vi) a coherent picture, where S to ssDNA
transitions are much more sensitive to base-pair sequence than the B to S one,
emerges.Comment: 14 pages, 9 figure
Early and Middle Holocene Hunter-Gatherer Occupations in Western Amazonia: The Hidden Shell Middens
We report on previously unknown early archaeological sites in the Bolivian lowlands, demonstrating for the first time early and middle Holocene human presence in western Amazonia. Multidisciplinary research in forest islands situated in seasonally-inundated savannahs has revealed stratified shell middens produced by human foragers as early as 10,000 years ago, making them the oldest archaeological sites in the region. The absence of stone resources and partial burial by recent alluvial sediments has meant that these kinds of deposits have, until now, remained unidentified. We conducted core sampling, archaeological excavations and an interdisciplinary study of the stratigraphy and recovered materials from three shell midden mounds. Based on multiple lines of evidence, including radiocarbon dating, sedimentary proxies (elements, steroids and black carbon), micromorphology and faunal analysis, we demonstrate the anthropogenic origin and antiquity of these sites. In a tropical and geomorphologically active landscape often considered challenging both for early human occupation and for the preservation of hunter-gatherer sites, the newly discovered shell middens provide evidence for early to middle Holocene occupation and illustrate the potential for identifying and interpreting early open-air archaeological sites in western Amazonia. The existence of early hunter-gatherer sites in the Bolivian lowlands sheds new light on the region's past and offers a new context within which the late Holocene "Earthmovers" of the Llanos de Moxos could have emerged. © 2013 Lombardo et al
DNA methylation in interleukin-11 predicts clinical response to antidepressants in GENDEP
Transcriptional differences in interleukin-11 (IL11) after antidepressant treatment have been found to correspond to clinical response in major depressive disorder (MDD) patients. Expression differences were partly mediated by a single-nucleotide polymorphism (rs1126757), identified as a predictor of antidepressant response as part of a genome-wide association study. Here we attempt to identify whether DNA methylation, another baseline factor known to affect transcription factor binding, might also predict antidepressant response, using samples collected from the Genome-based Therapeutic Drugs for Depression project (GENDEP). DNA samples from 113 MDD individuals from the GENDEP project, who were treated with either escitalopram (n=80) or nortriptyline (n=33) for 12 weeks, were randomly selected. Percentage change in Montgomery-� sberg Depression Rating Scale scores between baseline and week 12 were utilized as our measure of antidepressant response. The Sequenom EpiTYPER platform was used to assess DNA methylation across the only CpG island located in the IL11 gene. Regression analyses were then used to explore the relationship between CpG unit methylation and antidepressant response. We identified a CpG unit predictor of general antidepressant response, a drug by CpG unit interaction predictor of response, and a CpG unit by rs1126757 interaction predictor of antidepressant response. The current study is the first to investigate the potential utility of pharmaco-epigenetic biomarkers for the prediction of antidepressant response. Our results suggest that DNA methylation in IL11 might be useful in identifying those patients likely to respond to antidepressants, and if so, the best drug suited to each individual
Multiplicity Distributions and Charged-neutral Fluctuations
Results from the multiplicity distributions of inclusive photons and charged
particles, scaling of particle multiplicities, event-by-event multiplicity
fluctuations, and charged-neutral fluctuations in 158 GeV Pb+Pb
collisions are presented and discussed. A scaling of charged particle
multiplicity as and photons as have been observed, indicating violation of naive wounded nucleon model.
The analysis of localized charged-neutral fluctuation indicates a
model-independent demonstration of non-statistical fluctuations in both charged
particles and photons in limited azimuthal regions. However, no correlated
charged-neutral fluctuations are observed.Comment: Talk given at the International Symposium on Nuclear Physics
(ISNP-2000), Mumbai, India, 18-22 Dec 2000, Proceedings to be published in
Pramana, Journal of Physic
Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis
Gene expression profiling has been used previously with spinal cord homogenates and laser capture microdissected motor neurons to determine the mechanisms involved in neurodegeneration in amyotrophic lateral sclerosis. However, while cellular and animal model work has focused on superoxide dismutase 1-related amyotrophic lateral sclerosis, the transcriptional profile of human mutant superoxide dismutase 1 motor neurons has remained undiscovered. The aim of this study was to apply gene expression profiling to laser captured motor neurons from human superoxide dismutase 1-related amyotrophic lateral sclerosis and neurologically normal control cases, in order to determine those pathways dysregulated in human superoxide dismutase 1-related neurodegeneration and to establish potential pathways suitable for therapeutic intervention. Identified targets were then validated in cultured cell models using lentiviral vectors to manipulate the expression of key genes. Microarray analysis identified 1170 differentially expressed genes in spinal cord motor neurons from superoxide dismutase 1-related amyotrophic lateral sclerosis, compared with controls. These genes encoded for proteins in multiple functional categories, including those involved in cell survival and cell death. Further analysis determined that multiple genes involved in the phosphatidylinositol-3 kinase signalling cascade were differentially expressed in motor neurons that survived the disease process. Functional experiments in cultured cells and primary motor neurons demonstrate that manipulating this pathway by reducing the expression of a single upstream target, the negative phosphatidylinositol-3 kinase regulator phosphatase and tensin homology, promotes a marked pro-survival effect. Therefore, these data indicate that proteins in the phosphatidylinositol-3 kinase pathway could represent a target for therapeutic manipulation in motor neuron degeneration
Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR
Substantial experimental and theoretical efforts worldwide are devoted to
explore the phase diagram of strongly interacting matter. At LHC and top RHIC
energies, QCD matter is studied at very high temperatures and nearly vanishing
net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was
created at experiments at RHIC and LHC. The transition from the QGP back to the
hadron gas is found to be a smooth cross over. For larger net-baryon densities
and lower temperatures, it is expected that the QCD phase diagram exhibits a
rich structure, such as a first-order phase transition between hadronic and
partonic matter which terminates in a critical point, or exotic phases like
quarkyonic matter. The discovery of these landmarks would be a breakthrough in
our understanding of the strong interaction and is therefore in the focus of
various high-energy heavy-ion research programs. The Compressed Baryonic Matter
(CBM) experiment at FAIR will play a unique role in the exploration of the QCD
phase diagram in the region of high net-baryon densities, because it is
designed to run at unprecedented interaction rates. High-rate operation is the
key prerequisite for high-precision measurements of multi-differential
observables and of rare diagnostic probes which are sensitive to the dense
phase of the nuclear fireball. The goal of the CBM experiment at SIS100
(sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD
matter: the phase structure at large baryon-chemical potentials (mu_B > 500
MeV), effects of chiral symmetry, and the equation-of-state at high density as
it is expected to occur in the core of neutron stars. In this article, we
review the motivation for and the physics programme of CBM, including
activities before the start of data taking in 2022, in the context of the
worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal
Innate recognition of apoptotic cells:novel apoptotic cell-associated molecular patterns revealed by crossreactivity of anti-LPS antibodies
Cells dying by apoptosis are normally cleared by phagocytes through mechanisms that can suppress inflammation and immunity. Molecules of the innate immune system, the pattern recognition receptors (PRRs), are able to interact not only with conserved structures on microbes (pathogen-associated molecular patterns, PAMPs) but also with ligands displayed by apoptotic cells. We reasoned that PRRs might therefore interact with structures on apoptotic cells-apoptotic cell-associated molecular patterns (ACAMPs)-that are analogous to PAMPs. Here we show that certain monoclonal antibodies raised against the prototypic PAMP, lipopolysaccharide (LPS), can crossreact with apoptotic cells. We demonstrate that one such antibody interacts with a constitutively expressed intracellular protein, laminin-binding protein, which translocates to the cell surface during apoptosis and can interact with cells expressing the prototypic PRR, mCD14 as well as with CD14-negative cells. Anti-LPS cross reactive epitopes on apoptotic cells colocalised with annexin V-and C1q-binding sites on vesicular regions of apoptotic cell surfaces and were released associated with apoptotic cell-derived microvesicles (MVs). These results confirm that apoptotic cells and microbes can interact with the immune system through common elements and suggest that anti-PAMP antibodies could be used strategically to characterise novel ACAMPs associated not only with apoptotic cells but also with derived MVs
The role of the ubiquitination–proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer
Aberrant activity of growth factor receptors has been implicated in the pathogenesis of a wide variety of malignancies. The negative regulation of signaling by growth factor receptors is mediated in large part by the ubiquitination, internalization, and degradation of the activated receptor. Over the past few years, considerable insight into the mechanisms that control receptor downregulation has been gained. There are also data suggesting that mutations that lead to inhibition of downregulation of growth factor receptors could play a role in the pathogenesis of cancer. Therapies directed at enhancing the degradation of growth factor receptors offer a promising approach to the treatment of malignancies
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