3,711 research outputs found
A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries
Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration
Caffeine-induced synaptic potentiation in hippocampal CA2 neurons
Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A 1 adenosine receptors (A 1 Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. We found that physiological doses of caffeine in vivo or A 1 R antagonists in vitro induced robust, long-lasting potentiation of synaptic transmission in rat CA2 without affecting other regions of the hippocampus
Evidence for dark matter in the inner Milky Way
The ubiquitous presence of dark matter in the universe is today a central
tenet in modern cosmology and astrophysics. Ranging from the smallest galaxies
to the observable universe, the evidence for dark matter is compelling in
dwarfs, spiral galaxies, galaxy clusters as well as at cosmological scales.
However, it has been historically difficult to pin down the dark matter
contribution to the total mass density in the Milky Way, particularly in the
innermost regions of the Galaxy and in the solar neighbourhood. Here we present
an up-to-date compilation of Milky Way rotation curve measurements, and compare
it with state-of-the-art baryonic mass distribution models. We show that
current data strongly disfavour baryons as the sole contribution to the
galactic mass budget, even inside the solar circle. Our findings demonstrate
the existence of dark matter in the inner Galaxy while making no assumptions on
its distribution. We anticipate that this result will compel new
model-independent constraints on the dark matter local density and profile,
thus reducing uncertainties on direct and indirect dark matter searches, and
will shed new light on the structure and evolution of the Galaxy.Comment: First submitted version of letter published in Nature Physics on
Febuary 9, 2015:
http://www.nature.com/nphys/journal/vaop/ncurrent/full/nphys3237.htm
MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.
Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort
Plasmonically Enhanced Reflectance of Heat Radiation from Low-Bandgap Semiconductor Microinclusions
Increased reflectance from the inclusion of highly scattering particles at
low volume fractions in an insulating dielectric offers a promising way to
reduce radiative thermal losses at high temperatures. Here, we investigate
plasmonic resonance driven enhanced scattering from microinclusions of
low-bandgap semiconductors (InP, Si, Ge, PbS, InAs and Te) in an insulating
composite to tailor its infrared reflectance for minimizing thermal losses from
radiative transfer. To this end, we compute the spectral properties of the
microcomposites using Monte Carlo modeling and compare them with results from
Fresnel equations. The role of particle size-dependent Mie scattering and
absorption efficiencies, and, scattering anisotropy are studied to identify the
optimal microinclusion size and material parameters for maximizing the
reflectance of the thermal radiation. For composites with Si and Ge
microinclusions we obtain reflectance efficiencies of 57 - 65% for the incident
blackbody radiation from sources at temperatures in the range 400 - 1600
{\deg}C. Furthermore, we observe a broadbanding of the reflectance spectra from
the plasmonic resonances due to charge carriers generated from defect states
within the semiconductor bandgap. Our results thus open up the possibility of
developing efficient high-temperature thermal insulators through use of the
low-bandgap semiconductor microinclusions in insulating dielectrics.Comment: Main article (8 Figures and 2 Tables) + Supporting Information (8
Figures
Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer
Introduction
Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach.
Methods
Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39).
Results
Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1).
Conclusions
These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response
Structural Basis for Distinct Binding Properties of the Human Galectins to Thomsen-Friedenreich Antigen
The Thomsen-Friedenreich (TF or T) antigen, Galβ1-3GalNAcα1-O-Ser/Thr, is the core 1 structure of O-linked mucin type glycans appearing in tumor-associated glycosylation. The TF antigen occurs in about 90% of human cancer cells and is a potential ligand for the human endogenous galectins. It has been reported that human galectin-1 (Gal-1) and galectin-3 (Gal-3) can perform their cancer-related functions via specifically recognizing TF antigen. However, the detailed binding properties have not been clarified and structurally characterized. In this work, first we identified the distinct TF-binding abilities of Gal-1 and Gal-3. The affinity to TF antigen for Gal-3 is two orders of magnitude higher than that for Gal-1. The structures of Gal-3 carbohydrate recognition domain (CRD) complexed with TF antigen and derivatives, TFN and GM1, were then determined. These structures show a unique Glu-water-Arg-water motif-based mode as previously observed in the mushroom galectin AAL. The observation demonstrates that this recognition mode is commonly adopted by TF-binding galectins, either as endogenous or exogenous ones. The detailed structural comparisons between Gal-1 and Gal-3 CRD and mutagenesis experiments reveal that a pentad residue motif (51AHGDA55) at the loop (g1-L4) connecting β-strands 4 and 5 of Gal-1 produces a serious steric hindrance for TF binding. This motif is the main structural basis for Gal-1 with the low affinity to TF antigen. These findings provide the intrinsic structural elements for regulating the TF-binding activity of Gal-1 in some special conditions and also show certain target and approach for mediating some tumor-related bioactivities of human galectins
Microbial ligand costimulation drives neutrophilic steroid-refractory asthma
Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD
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