Parallel Computing for Brain Simulation Pastur-Romay, L A; Porto-Pazos, A B; Cedron, F ...
Current topics in medicinal chemistry,
05/2017, Letnik:
17, Številka:
14
Journal Article
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The human brain is the most complex system in the known universe, it is therefore one of the greatest mysteries. It provides human beings with extraordinary abilities. However, until now it has not ...been understood yet how and why most of these abilities are produced.
For decades, researchers have been trying to make computers reproduce these abilities, focusing on both understanding the nervous system and, on processing data in a more efficient way than before. Their aim is to make computers process information similarly to the brain. Important technological developments and vast multidisciplinary projects have allowed creating the first simulation with a number of neurons similar to that of a human brain.
This paper presents an up-to-date review about the main research projects that are trying to simulate and/or emulate the human brain. They employ different types of computational models using parallel computing: digital models, analog models and hybrid models. This review includes the current applications of these works, as well as future trends. It is focused on various works that look for advanced progress in Neuroscience and still others which seek new discoveries in Computer Science (neuromorphic hardware, machine learning techniques). Their most outstanding characteristics are summarized and the latest advances and future plans are presented. In addition, this review points out the importance of considering not only neurons: Computational models of the brain should also include glial cells, given the proven importance of astrocytes in information processing.
Interplay between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of ...systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 145 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex composition and function, and predict new functional interactions, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality.
The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug ...delivery systems. The encapsulation enables mitigating the drugs' side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess
and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity
from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with
= 24, there are two other competing contributions that enable increasing
under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. The in vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cells, and low activity against healthy MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.
Preclinical studies support a critical role of 5-HT4 receptors (5-HT4Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants ...remain partly unknown. We evaluated 5-HT4R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT1AR. Moreover, the implication of 5-HT4Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT4R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT4R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT4R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT4R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT4Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT4Rs.
•The absence of 5-HT4Rs modulates depression- and anxiety-responses in mice.•Fluoxetine failed to reverse OBX-induced syndrome in 5-HT4R KO mice.•Fluoxetine reduced hippocampal Arc and BDNF in OBX-WT but not in OBX-5-HT4R KO mice.
Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a ...result, ~80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive-like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant-like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies.
Seasonal variations in the body weight and biochemical composition of the bivalve
Ruditapes decussatus were studied over a period of 15 months. Separate analyses were made of foot, mantle edge, ...siphons, gills, adductor muscle and gonad-visceral mass. Variations in weight, body growth, gonad growth and spawning depended on environmental conditions, especially food availability. The gametogenic cycle comprised two phases: a resting phase (November–December) and gametogenesis, including ripeness and spawning, during the rest of the year. Gametogenesis usually took place during the spring, and spawning in summer (June–August). The highest variation in biochemical composition was largely attributable to a change in the glycogen content (average 14.7%±5.1 S.D. of dry weight). Protein (48.1%±1.8) and lipid contents (5.6%±0.6) remained relatively constant throughout the year. Adductor muscle, foot and siphons contained mainly proteins (67.8%, 51.2% and 65.8% of the dry tissue weight, respectively) and gonad-visceral mass and gills contained the highest amount of lipids (≈7%). The gonad-visceral mass showed the largest variations in all components during the gametogenic cycle. Lipid and glycogen concentrations in the gonad-visceral mass were inversely related: maximum concentrations of glycogen occurred during the resting phase or initial gametogenesis and corresponded with minimum concentrations of lipids, and minimum concentrations of glycogen occurred at maturity when lipids reached maximum concentrations. The gonad-visceral mass contained lower amounts of proteins (<40%) than the other body parts. Variations in total fatty acid content in neutral and polar lipids of the gonad-visceral mass followed a seasonal cycle related to the gametogenic cycle, with increases during the period of maximum ripeness and decreases during spawnings. Maximal contents of polyunsaturated fatty acids, especially in the polar lipids corresponded with oocyte maturation and minimal contents with the post-spawning period. However, variations in the neutral lipids appeared to be related to the available food, in association with an increase in the chlorophyll
a concentration.
Nowadays the Heat Pump is one of the best systems to warm a building with a good performance. Usually, with the aim to increase the efficiency, a geothermal heat exchanger is added to the ...installation. This component shows a disturbing effect on the ground where it is placed. On this research a bio-inspired system was developed to test the ground temperature behavior where there is a heat exchanger. The novel approach has been implemented and tested under a real dataset. One year temperature measurements were recorded. The final approach is based on clustering and regression techniques. Then, the model was validated and tested with a dataset from a real installation with a good performance.
Pregnancy is a leading risk factor for severe complications during an influenza virus infection. Women infected during their second and third trimesters are at increased risk for severe ...cardiopulmonary complications, premature delivery, and death. Here, we establish a murine model of aerosolized influenza infection during pregnancy. We find significantly altered innate antiviral responses in pregnant mice, including decreased levels of IFN-β, IL-1α, and IFN-γ at early time points of infection. We also find reduced cytotoxic T cell activity and delayed viral clearance. We further demonstrate that pregnancy levels of the estrogen 17-β-estradiol are able to induce key anti-inflammatory phenotypes in immune responses to the virus independently of other hormones or pregnancy-related stressors. We conclude that elevated estrogen levels result in an attenuated anti-viral immune response, and that pregnancy-associated morbidities occur in the context of this anti-inflammatory phenotype.
Neutrophil breach of the mucosal surface is a common pathological consequence of infection. We present an advanced co-culture model to explore neutrophil transepithelial migration utilizing airway ...mucosal barriers differentiated from primary human airway basal cells and examined by advanced imaging. Human airway basal cells were differentiated and cultured at air-liquid interface (ALI) on the underside of 3 µm pore-sized transwells, compatible with the study of transmigrating neutrophils. Inverted ALIs exhibit beating cilia and mucus production, consistent with conventional ALIs, as visualized by micro-optical coherence tomography (µOCT). µOCT is a recently developed imaging modality with the capacity for real time two- and three-dimensional analysis of cellular events in marked detail, including neutrophil transmigratory dynamics. Further, the newly devised and imaged primary co-culture model recapitulates key molecular mechanisms that underlie bacteria-induced neutrophil transepithelial migration previously characterized using cell line-based models. Neutrophils respond to imposed chemotactic gradients, and migrate in response to Pseudomonas aeruginosa infection of primary ALI barriers through a hepoxilin A3-directed mechanism. This primary cell-based co-culture system combined with µOCT imaging offers significant opportunity to probe, in great detail, micro-anatomical and mechanistic features of bacteria-induced neutrophil transepithelial migration and other important immunological and physiological processes at the mucosal surface.
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