The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible ...factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.
Comparative evolutionary analysis of whole genomes requires not only accurate annotation of gene space, but also proper annotation of the repetitive fraction which is often the largest component of ...most if not all genomes larger than 50 kb in size.
Here we present the Rice TE database (RiTE-db)--a genus-wide collection of transposable elements and repeated sequences across 11 diploid species of the genus Oryza and the closely-related out-group Leersia perrieri. The database consists of more than 170,000 entries divided into three main types: (i) a classified and curated set of publicly-available repeated sequences, (ii) a set of consensus assemblies of highly-repetitive sequences obtained from genome sequencing surveys of 12 species; and (iii) a set of full-length TEs, identified and extracted from 12 whole genome assemblies.
This is the first report of a repeat dataset that spans the majority of repeat variability within an entire genus, and one that includes complete elements as well as unassembled repeats. The database allows sequence browsing, downloading, and similarity searches. Because of the strategy adopted, the RiTE-db opens a new path to unprecedented direct comparative studies that span the entire nuclear repeat content of 15 million years of Oryza diversity.
The rapid development of optoelectronic applications for optical-to-electrical conversion has increased the interest in graphene oxide material. Here, graphene oxide films (GOF) were used as source ...material in an infrared photodetector configuration and the temperature dependence of the electrical conductivity was studied. GOF were prepared by the double-thermal decomposition (DTD) method at 973 K, with a fixed carbonization temperature, in a pyrolysis system, under a controlled nitrogen atmosphere, over quartz substrates. Graphene oxide films were mechanically supported in a photodetector configuration on Bakelite substrates and electrically contacted with copper wires and high-purity silver paint. Morphological images from the GOF's surface were taken employing a scanning electron microscope and observed a homogeneous surface which favored the electrical contacts deposition. Vibrational characteristics were studied employing Raman spectroscopy and determined the typical graphene oxide bands. GOF were used to discuss the effect of temperature on the film's electrical conductivity. Current-voltage (I-V) curves were taken for several temperatures varying from 20 to 300 K and the electrical resistance values were obtained from 142.86 to 2.14 kΩ. The GOF electrical conductivity and bandgap energy (E
) were calculated, and it was found that when increasing temperature, the electrical conductivity increased from 30.33 to 2023.97 S/m, similar to a semiconductor material, and E
shows a nonlinear change from 0.33 to 0.12 eV, with the increasing temperature. Conduction mechanism was described mainly by three-dimensional variable range hopping (3D VRH). Additionally, measurements of voltage and electrical resistance, as a function of wavelength were considered, for a spectral range between 1300 and 3000 nm. It was evidenced that as the wavelength becomes longer, a greater number of free electrons are generated, which contributes to the electrical current. The external quantum efficiency (EQE) was determined for this proposed photodetector prototype, obtaining a value of 40%, similar to those reported for commercial semiconductor photodetectors. This study provides a groundwork for further development of graphene oxide films with high conductivity in large-scale preparation.
Ixodid ticks are ectoparasites that feed exclusively on blood as their source of nutrients. Although ticks spend most of their life off the host, until now it has been assumed that the blood and the ...water vapor are the only sources of water to maintain water balance and prevent desiccation. Here we report for the first time that adult lone star ticks, Amblyomma americanum, also actively drink nutrient-free water, which greatly increases their survival. The volume of ingested water is greater in females than males (0.55 ± 0.06 vs 0.44 ± 0.07 µl) and most likely due to differences in tick size. Water uptake occurs through mouthparts and it can be later observed in the salivary glands and the midgut. We also exploited this behavior by adding a variety of inorganic compounds and microorganisms to water. Addition of inorganic salts to drinking water such as KH
PO
+ NaCl+KNO
resulted in 100% tick mortality within 3 days. As a proof of concept for using the water drinking as a delivery route of toxic reagents for ticks, we also show that adding Pseudomonas aeruginosa to drinking water quickly leads to tick death. This tick behavior can be exploited to target important physiological systems, which would make ticks vulnerable to dehydration and microbial dysbiosis.
The anatomy and functional role of the inferior fronto-occipital fascicle (IFOF) remain poorly known. We accurately analyze its course and the anatomical distribution of its frontal terminations. We ...propose a classification of the IFOF in different subcomponents. Ten hemispheres (5 left, 5 right) were dissected with Klingler’s technique. In addition to the IFOF dissection, we performed a 4-T diffusion tensor imaging study on a single healthy subject. We identified two layers of IFOF. The first one is superficial and antero-superiorly directed, terminating in the inferior frontal gyrus. The second is deeper and consists of three portions: posterior, middle and anterior. The posterior component terminates in the middle frontal gyrus (MFG) and dorso-lateral prefrontal cortex. The middle component terminates in the MFG and lateral orbito-frontal cortex. The anterior one is directed to the orbito-frontal cortex and frontal pole. In vivo tractography study confirmed these anatomical findings. We suggest that the distribution of IFOF fibers within the frontal lobe corresponds to a fine functional segmentation. IFOF can be considered as a “multi-function” bundle, with each anatomical subcomponent subserving different brain processing. The superficial layer and the posterior component of the deep layer, which connects the occipital extrastriate, temporo-basal and inferior frontal cortices, might subserve semantic processing. The middle component of the deep layer could play a role in a multimodal sensory–motor integration. Finally, the anterior component of the deep layer might be involved in emotional and behavioral aspects.
In December 2019, rising pneumonia cases caused by a novel β-coronavirus (SARS-CoV-2) occurred in Wuhan, China, which has rapidly spread worldwide, causing thousands of deaths. The WHO declared the ...SARS-CoV-2 outbreak as a public health emergency of international concern, since then several scientists are dedicated to its study. It has been observed that many human viruses have codon usage biases that match highly expressed proteins in the tissues they infect and depend on the host cell machinery for the replication and co-evolution. In this work, we analysed 91 molecular features and codon usage patterns for 339 viral genes and 463 human genes that consisted of 677,873 codon positions. Hereby, we selected the highly expressed genes from human lung tissue to perform computational studies that permit to compare their molecular features with those of SARS, SARS-CoV-2 and MERS genes. The integrated analysis of all the features revealed that certain viral genes and overexpressed human genes have similar codon usage patterns. The main pattern was the A/T bias that together with other features could propitiate the viral infection, enhanced by a host dependant specialization of the translation machinery of only some of the overexpressed genes. The envelope protein E, the membrane glycoprotein M and ORF7 could be further benefited. This could be the key for a facilitated translation and viral replication conducting to different comorbidities depending on the genetic variability of population due to the host translation machinery. This is the first codon usage approach that reveals which human genes could be potentially deregulated due to the codon usage similarities between the host and the viral genes when the virus is already inside the human cells of the lung tissues. Our work leaded to the identification of additional highly expressed human genes which are not the usual suspects but might play a role in the viral infection and settle the basis for further research in the field of human genetics associated with new viral infections. To identify the genes that could be deregulated under a viral infection is important to predict the collateral effects and determine which individuals would be more susceptible based on their genetic features and comorbidities associated.
Determinants of BRAF mutations in primary melanomas MALDONADO, Janet L; FRIDLYAND, Jane; PATEL, Hetal ...
JNCI : Journal of the National Cancer Institute,
12/2003, Letnik:
95, Številka:
24
Journal Article
Recenzirano
Odprti dostop
The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine kinase in this pathway, is frequently activated by somatic ...mutation in melanoma. Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher's exact test). By contrast, BRAF mutations in melanomas on chronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively or completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 patients), and mucosal membranes (2 of 21 patients) are rare. We found no association of mutation status with clinical outcome or with the presence of an associated melanocytic nevus. The mutated BRAF allele was frequently found at an elevated copy number, implicating BRAF as one of the factors driving selection for the frequent copy number increases of chromosome 7q in melanoma. In summary, the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma. The high mutation frequency in melanomas arising on intermittently sun-exposed skin suggests a complex causative role of such exposure that mandates further evaluation.
Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising ...strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 4-2-(4-chlorophenyl)ethyl-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.
•SA-57 inhibits fatty acid amide hydrolase and monoacylglycerol lipase.•SA-57 reverses allodynia in mouse neuropathic and inflammatory pain models.•CB1 and CB2 receptors mediate the antinociceptive effects of SA-57 in the carrageenan model of inflammatory pain.•SA-57 enhances morphine-induced antinociception.•SA-57 reduces heroin self-administration.
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•BSA and PDL form spherical coacervate nanoparticles around 200–300nm.•The particle size and polydispersity depend on pH, mass ratio, MW and ionic strength.•Positive zeta potential ...indicates that PDLs are located on the surface of NPs.•Hydrophobic bioactive curcumin was successfully encapsulated in the NPs.•Curcumin loaded NPs were stable over 21day’s storage.
Soluble coacervate nanoparticles were fabricated by mixing bovine serum albumin (BSA) and poly-d-lysine with low (LMW-PDL) and high molecular weights (HMW-PDL). The particle size was influenced by molecular weight, mass ratio of polyelectrolytes (PEs), and salt concentration. The smallest nanoparticles had a diameter of 212±11nm which was achieved with LMW-PDL dissolved with 0.1M NaCl at pH 7 and a mass ratio of 2.0 (BSA: PDL). SEM images showed that coacervate nanoparticles of LMW-PDL are relatively spherical in shape, while nanoparticles of HMW-PDL were irregular. Crosslinking of the protein/polypeptide with glutaraldehyde had variable impact on the stability and particle size over 21days at 4 and 25°C. The encapsulation efficiency (EE) for curcumin to BSA molar ratio of 0.5 was 47%. The EE increased to 60% when the curcumin to BSA molar ratio was 10 with a loading capacity of 22μg of curcumin per mg of coacervate nanoparticles. The average particle size of the loaded colloidal dispersions increased as the curcumin concentration was increased. For the colloidal dispersions with 0.5 molar ratio of curcumin to BSA, the particle size was around 204±14nm at day 1, while the nanoparticles with molar ratio of 10 showed a particle size around 316±43nm. The curcumin loaded BSA:LMW-PDL nanoparticles were pretty stable over a period of 21days.
Autonomous systems must be able to adapt to a constantly-changing environment. This adaptability requires significant computational resources devoted to learning, and current artificial systems are ...lacking in these resources when compared to humans and animals. We aim to produce VLSI spiking neural networks which feature learning structures similar to those in biology, with the goal of achieving the performance and efficiency of natural systems. The neuroscience literature suggests that calcium ions play a key role in explaining long-term synaptic plasticity's dependence on multiple factors, such as spike timing and stimulus frequency. Here we present a novel VLSI implementation of a calcium-based synaptic plasticity model, comparisons between the model and circuit simulations, and measurements of the fabricated circuit.
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