The Cross-Talk Between Neurons and Microglia Through Interleukin-4 After Ischemic Injury

After ischemic stroke, the loss of blood supply to the affected region of the brain leads to a series of pathological events known as ischemic cascades, that include excitotoxicity and microglia/macrophage over-activation resulting in damaging inflammatory responses. Studies from our research group suggest that the viable neurons in the ischemic penumbra (location receiving less profound damage, as compare to ischemic core) produce and release a potent anti-inflammatory cytokine, interleukin(IL) -4. We propose that this neuronal response to sublethal ischemia is designed to guide surrounding microglia/macrophages to a reparative and anti-inflammatory (M2) phenotype. The research included in this study is designed to establish the mechanisms that underlie neuronal production and secretion of IL-4 under ischemic injury. To investigate this process we used primary rat cortical neurons in culture and a well-validated in vitro ischemic injury model that is based on transient oxygen- and glucose- deprivation, (OGD). In this model, only longer durations of OGD result in neuronal death. We discover that short-duration, sublethal OGD, as determined by LDH release assay, more LDH release correspond to greater damage) induces neuronal IL-4 production at the gene (RT-qPCR) and protein (ELISA) level. Furthermore, we show that mild excitotoxic stress produced by N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation (process that normally occurs in the cerebral ischemia) triggers IL-4 production and release by neurons in the primary neuron culture. We also implicated calcineurin and nuclear factor of activated T cell (NFAT) as potential players in the transcriptional regulation of the IL-4 synthesis in neurons. Finally, using neuron conditioned medium transfer to microglia, we find that neuronal IL-4 is capable of polarizing microglia toward a restorative, anti-inflammatory, and phagocytic phenotype. For the first time, this study demonstrates that the ischemia-evoked NMDAR activation, through calcineurin/NFAT pathway induces IL-4 production by neurons, and that this neuron-secreted IL-4 is capable of regulating microglia phenotype change. This cross-talk between neurons and microglia could represent a therapeutic target for cerebral ischemia

Supervised Collective Classification for Crowdsourcing

Crowdsourcing utilizes the wisdom of crowds for collective classification via information (e.g., labels of an item) provided by labelers. Current crowdsourcing algorithms are mainly unsupervised methods that are unaware of the quality of crowdsourced data. In this paper, we propose a supervised collective classification algorithm that aims to identify reliable labelers from the training data (e.g., items with known labels). The reliability (i.e., weighting factor) of each labeler is determined via a saddle point algorithm. The results on several crowdsourced data show that supervised methods can achieve better classification accuracy than unsupervised methods, and our proposed method outperforms other algorithms.Comment: to appear in IEEE Global Communications Conference (GLOBECOM) Workshop on Networking and Collaboration Issues for the Internet of Everythin

Brain Cleanup as a Potential Target for Poststroke Recovery: The Role of RXR (Retinoic X Receptor) in Phagocytes

Background and Purpose- Phagocytic cells, such as microglia and blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that are compromised during senescence or pathological processes, including after stroke. This process of clearance is essential to eliminate the source of inflammation and to allow for optimal brain repair and functional recovery. Transcription factor, RXR (retinoic-X-receptor) is strongly implicated in phagocytic functions regulation, and as such could represent a novel target for brain recovery after stroke. Methods- Primary cultured microglia and bone marrow macrophages were used for phagocytic study. Mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α-/-) were subjected to transient middle cerebral artery occlusion to mimic ischemic stroke and then treated with RXR agonist bexarotene. RNA-sequencing and long-term recovery were evaluated. Results- Using cultured microglia, we demonstrated that the RXR-α promotes the phagocytic functions of microglia toward apoptotic neurons. Using mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α-/-), we have shown that despite behaving similarly to the control at early time points (up to 3 days, damage established histologically and behaviorally), these Mac-RXR-α-/- mice demonstrated worsened late functional recovery and developed brain atrophy that was larger in size than that seen in control mice. The RXR-α deficiency was associated with reduced expression of genes known to be under control of the prominent transcriptional RXR partner, PPAR (peroxisome proliferator-activated receptor)-γ, as well as genes encoding for scavenger receptors and genes that signify microglia/macrophages polarization to a reparative phenotype. Finally, we demonstrated that the RXR agonist, bexarotene, administered as late as 1 day after middle cerebral artery occlusion, improved neurological recovery, and reduced the atrophy volume as assessed 28 days after stroke. Bexarotene did not improve outcome in Mac-RXR-α-/- mice. Conclusions- Altogether, these data suggest that phagocytic cells control poststroke recovery and that RXR in these cells represents an attractive target with exceptionally long therapeutic window.This work was supported by grant from the National Institutes of Health (NINDS) 1R01NS084292 to Dr Aronowski. Additional funding from Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU) (SAF2017-90604-REDT-NurCaMeln, RTI2018-095928-B-I00) to Dr Ricote permitted to study RXR (retinoic-X-receptor) deletion in the phagocytic cells. The Centro Nacional de Investigaciones Cardiovasculares is supported by the Instituto de Salud Carlos III (ISCIII), the MCNU, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Comprehensive study of the blazars from Fermi-LAT LCR: The log-normal flux distribution and linear RMS-Flux relation

Fermi-LAT LCR provide continuous and regularly-sampled gamma-ray light curves, spanning about 14 years, for a large sample of blazars. The log-normal flux distribution and linear RMS-Flux relation of the light curves for a few of Fermi blazar have been examined in previous studies. However, the probability that blazars exhibit log-normal flux distribution and linear RMS-Flux relation in their gamma-ray light curves has not been systematically explored. In this study, we comprehensively research on the distribution of gamma-ray flux and the statistical characteristics on a large sample of 1414 variable blazars from the Fermi-LAT LCR catalog, including 572 FSRQs, 477 BL Lacs, and 365 BCUs, and statistically compare their flux distributions with normal and log-normal distributions. The results indicate that the probability of not reject log-normal is 42.05% for the large sample, and there is still 2.05% probability of not reject normality, based on the joint of Kolmogorov-Smirnov, Shapiro-Wilk and Normality tests. We further find that the probability that BL Lacs conforms to the log-normal distribution is higher than that of FSRQs. Besides, after removing sources with less than 200 data points from this large sample, a sample of 549 blazars, which is still a large sample comparing to the previous studies, was obtained. Basing on dividing the light curves into segments every 20 points (or 40 points, or one year), we fitted the linear RMS-Flux relation of this three different sets, and found that the Pearson correlation coefficients are all close to 1 of the most blazars. This result indicates a strong linear correlation between the RMS and the flux of this 549 blazars. The log-normal distribution and linear RMS-Flux relation indicate that the variability of gamma-ray flux for most blazars is non-linear and multiplicative process.Comment: 13pages, 5figures, Accepted for publication in RA

DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3β in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia

Immobilization of enzyme and antibody on ALD-HfO2-EIS structure by NH3 plasma treatment

Thin hafnium oxide layers deposited by an atomic layer deposition system were investigated as the sensing membrane of the electrolyte-insulator-semiconductor structure. Moreover, a post-remote NH3 plasma treatment was proposed to replace the complicated silanization procedure for enzyme immobilization. Compared to conventional methods using chemical procedures, remote NH3 plasma treatment reduces the processing steps and time. The results exhibited that urea and antigen can be successfully detected, which indicated that the immobilization process is correct

Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer

AbstractStatins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and ApcMin/+ CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC