BackgroundOxidative stress plays an important and causal role in the mechanisms by which ischemia/reperfusion (I/R) injury increases brain damage after stroke. Accordingly, reducing oxidative stress has been proposed as a therapeutic strategy for limiting damage in the brain after stroke. Myeloperoxidase (MPO) is a highly potent oxidative enzyme that is capable of inducing both oxidative and nitrosative stress in vivo.MethodsTo determine if and the extent to which MPO-generated oxidants contribute to brain I/R injury, we treated mice subjected to middle cerebral artery occlusion (MCAO) with N-acetyl lysyltyrosylcysteine amide (KYC), a novel, specific and non-toxic inhibitor of MPO. Behavioral testing, ischemic damage, blood-brain-barrier disruption, apoptosis, neutrophils infiltration, microglia/macrophage activation, and MPO oxidation were analyzed within a 7-day period after MCAO.ResultsOur studies show that KYC treatment significantly reduces neurological severity scores, infarct size, IgG extravasation, neutrophil infiltration, loss of neurons, apoptosis, and microglia/macrophage activation in the brains of MCAO mice. Immunofluorescence studies show that KYC treatment reduces the formation of chlorotyrosine (ClTyr), a fingerprint biomarker of MPO oxidation, nitrotyrosine (NO2Tyr), and 4-hydroxynonenal (4HNE) in MCAO mice. All oxidative products colocalized with MPO in the infarcted brains, suggesting that MPO-generated oxidants are involved in forming the oxidative products.ConclusionsMPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0583-x) contains supplementary material, which is available to authorized users.
Abstract:Interleukin-1 (IL-1) is one of the first cytokines ever described. It has long been recognized to play an important role in mediating inflammation and orchestrating the physiological and behavioral adjustments that occur during sickness.Recently, accumulating evidence has indicated that IL-1 also adversely affects cognitive function. Nevertheless, there are also some reports showing no effects or even beneficial effects of IL-1 on learning and memory. The relationship between IL-1 and cognitive impairment has not been clearly elucidated. Here we reviewed the evidence of both negative and positive effects of IL-1 on learning and memory, and the key factors that may affect the effects of IL-1 on learning and memory were discussed.
Motivation The acid dissociation constant (pKa) is a critical parameter to reflect the ionization ability of chemical compounds and is widely applied in a variety of industries. However, the experimental determination of pKa is intricate and time-consuming, especially for the exact determination of micro pKa information at the atomic level. Hence, a fast and accurate prediction of pKa values of chemical compounds is of broad interest. Results Here, we compiled a large scale pKa dataset containing 16595 compounds with 17489 pKa values. Based on this dataset, a novel pK a prediction model, named Graph-pKa, was established using graph neural networks. Graph-pKa performed well on the prediction of macro pK a values, with a mean absolute error around 0.55 and a coefficient of determination around 0.92 on the test dataset. Furthermore, combining multi-instance learning, Graph-pKa was also able to automatically deconvolute the predicted macro pKa into discrete micro pK a values. Availability The Graph-pK a model is now freely accessible via a web-based interface (https://pka.simm.ac.cn/). Supplementary information Supplementary data are available at Bioinformatics online.
Mitral cells (MCs) contained in the main (MOB) and accessory (AOB) olfactory bulb have distinct intrinsic membrane properties but the extent of neuromodulation across the two systems has not been widely explored. Herein, we investigated a widely distributed CNS modulator, serotonin (5-HT), for its ability to modulate the biophysical properties of MCs across the MOB and AOB, using an in vitro, brain slice approach in postnatal 15-30 day mice. In the MOB, 5-HT elicited three types of responses in 93% of 180 cells tested. Cells were either directly excited (70%), inhibited (10%) or showed a mixed response (13%)- first inhibition followed by excitation. In the AOB, 82% of 148 cells were inhibited with 18% of cells showing no response. Albeit located in parallel partitions of the olfactory system, 5-HT largely elicited MC excitation in the MOB while it evoked two different kinetic rates of MC inhibition in the AOB. Using a combination of pharmacological agents, we found that the MC excitatory responses in the MOB were mediated by 5-HT receptors through a direct activation. In comparison, 5-HT-evoked inhibitory responses in the AOB arose due to a polysynaptic, slow-onset inhibition attributed to 5-HT receptor activation exciting GABAergic interneurons. The second type of inhibition had a rapid onset as a result of direct inhibition mediated by the 5-HT class of receptors. The distinct serotonergic modulation of MCs between the MOB and AOB could provide a molecular basis for differential chemosensory behaviours driven by the brainstem raphe nuclei into these parallel systems.
Retinoic acid (RA) plays multiple roles in the nervous system, including induction of neural differentiation, axon outgrowth and neural patterning. Previously, RA for neural differentiation of embryonic stem (ES) cells always relies on embryoid bodies (EBs) formation. Here we report an in vitro adherent monoculture system to induce mouse ES cells into neural cells accompanied with RA. RA (1 μM) treatment, during initial 2 days of differentiation, can enhance the expression of neural markers, such as Nestin, Tuj1 and MAP2, and result in an earlier neural differentiation of ES cells. Furthermore, RA promotes a significant increase in neurite elongation of ES-derived neurons. Our study also implies that RA induced to express Wnt antagonist Dickkopf-1 (Dkk-1) for neural differentiation. However, the mechanisms of RA triggering neural induction remain to be determined. Our simple and efficient strategy is proposed to provide a basis for studying RA signaling pathways in neural differentiation in vitro.
Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3−∕−) results in “Super-smeller” mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3−∕− mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3−∕− male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3−∕− mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3−∕− mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.
Automated story generation is a challenging task which aims to automatically generate convincing stories composed of successive plots correlated with consistent characters. Most recent generation models are built upon advanced neural networks, e.g., variational autoencoder, generative adversarial network, convolutional sequence to sequence model. Although these models have achieved prompting results on learning linguistic patterns, very few methods consider the attributes and prior knowledge of the story genre, especially from the perspectives of explainability and consistency. To fill this gap, we propose a character-centric neural storytelling model, where a story is created encircling the given character, i.e., each part of a story is conditioned on a given character and corresponded context environment. In this way, we explicitly capture the character information and the relations between plots and characters to improve explainability and consistency. Experimental results on open dataset indicate that our model yields meaningful improvements over several strong baselines on both human and automatic evaluations.
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