CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

The roles of chemokine C-X-C motif ligand 12 (CXCL12) and its receptor chemokine C-X-C motif receptor 4 (CXCR4) reveal this chemokine axis as an emerging neuromodulator in the nervous system. In the peripheral and central nervous systems, both CXCL12 and CXCR4 are expressed in various kinds of nociceptive structures, and CXCL12/CXCR4 axis possesses pronociceptive property. Recent studies have demonstrated its critical roles in the development and maintenance of pathological pain, and both neuronal and glial mechanisms are involved in this CXCL12/CXCR4 axis-mediated pain processing. In this review, we summarize the recent development of the roles and mechanisms of CXCL12/CXCR4 axis in the pathogenesis of chronic pain by sciatic nerve injury, human immunodeficiency virus-associated sensory neuropathy, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia. The potential targeting of CXCL12/CXCR4 axis as an effective and broad-spectrum pharmacological approach for chronic pain therapy was also discussed.published_or_final_versio

Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain

published_or_final_versio

Central administration of C-x-C chemokine receptor type 4 antagonist alleviates the development and maintenance of peripheral neuropathic pain in mice

Aim To explore the roles of C-X-C chemokine receptor type 4 (CXCR4) in spinal processing of neuropathic pain at the central nervous system (CNS). Methods Peripheral neuropathic pain (PNP) induced by partial sciatic nerve ligation (pSNL) model was assessed in mice. Effects of a single intrathecal (central) administration of AMD3100 (intrathecal AMD3100), a CXCR4 antagonist, on pain behavior and pain-related spinal pathways and molecules in the L3-L5 spinal cord segment was studied compare to saline treatment. Results Rotarod test showed that intrathecal AMD3100 did not impair mice motor function. In pSNL-induced mice, intrathecal AMD3100 delayed the development of mechanical allodynia and reversed the established mechanical allodynia in a dose-dependent way. Moreover, intrathecal AMD3100 downregulated the activation of JNK1 and p38 pathways and the protein expression of p65 as assessed by western blotting. Real-time PCR test also demonstrated that substance P mRNA was decreased, while adrenomedullin and intercellular adhesion molecule mRNA was increased following AMD3100 treatment. Conclusion Our results suggest that central (spinal) CXCR4 is involved in the development and maintenance of PNP and the regulation of multiple spinal molecular events under pain condition, implicating that CXCR4 would potentially be a therapeutic target for chronic neuropathic pain.published_or_final_versio

Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. © 2013 Thyagarajan et al

Ischemia postconditioning attenuates myocardial ischemia reperfusion injury by upregulating cardiac adiponectin expression in mice

Poster sessionIschemic heart disease (IHD) remains the leading cause of mortality and morbidity in diabetic patients. Ischemia postconditioning (IPostC) has been shown to be a effective way in combating myocardial ischemia-reperfusion injury, but the cardioprotective effects of IpostC is compromised or diminished in patients with diabetes, a metabolic disease that was associated with reduced levels of adiponectin (APN). Adiponectin (APN) is a protein that is secreted primarily from adipose tissue, which confers cardioprotection by enhancing myocardial nitric oxide production, a key mediator in IPostCcardioprotection, however, its role in IPostC mediated cardioprotection has not been investigated. The aims of the present study were to determine the role of APN in IPostC mediated cardioprotective effect and investigate the underlying molecular mechanisms. Wild-type (WT) and APN knockout (AKO) mice were subjected to 30 min coronary artery ligation followed by 2 hours of reperfusion, at the absent or present of IPostC achieved by 3 episodes of 10s reperfusion and 10s re-occlusion immediately after ischemia. Myocardial functions were assessed by pressure volume (PV) conductance system. Post-ischemic myocardial infarct size was higher in AKO relative to WT, which was associate with significant reduction of myocardial p-eNOS expression and end systolic PV relation, a reliable measure of ventricular systolic function, in AKO. In contrast, IPostC significantly reduce infarct size and improve end systolic PV relation, together with significant increase expression of myocardial APN, in WT but not in AKO. It is concluded that enhancement of myocardial APN may represent a key mechanism by which IPostC confers cardioprotection.published_or_final_versio

Robust optical delay lines via topological protection

Phenomena associated with topological properties of physical systems are naturally robust against perturbations. This robustness is exemplified by quantized conductance and edge state transport in the quantum Hall and quantum spin Hall effects. Here we show how exploiting topological properties of optical systems can be used to implement robust photonic devices. We demonstrate how quantum spin Hall Hamiltonians can be created with linear optical elements using a network of coupled resonator optical waveguides (CROW) in two dimensions. We find that key features of quantum Hall systems, including the characteristic Hofstadter butterfly and robust edge state transport, can be obtained in such systems. As a specific application, we show that the topological protection can be used to dramatically improve the performance of optical delay lines and to overcome limitations related to disorder in photonic technologies.Comment: 9 pages, 5 figures + 12 pages of supplementary informatio

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4

The small ubiquitin-like modifier (SUMO) can form polymeric chains that are important signals in cellular processes such as meiosis, genome maintenance and stress response. The SUMO-targeted ubiquitin ligase RNF4 engages with SUMO chains on linked substrates and catalyses their ubiquitination, which targets substrates for proteasomal degradation. Here we use a segmental labelling approach combined with solution nuclear magnetic resonance (NMR) spectroscopy and biochemical characterization to reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer

Identification of vocal individuality in male cuckoos using different analytical techniques

© 2017 The Author(s). Background: Individuality in vocalizations may provide an effective tool for surveying populations of the Common Cuckoo (Cuculus canorus) but there remains few data on which technique to use to identify individuality. In this research, we compared the within- and between-individual variation in cuckoo calls using two different analytical methods, and discuss the feasibility of using call individuality to count male cuckoos within a population. Methods: We recorded vocalization from 13 males, and measured 15 spectro-temporal variables for each call. The majority of these call variables (n=12) have greater variation between individuals than within individual. We first calculated the similarity (Pearson's R) for each paired calls in order to find a threshold that could distinguish calls emitted from the same or different males, and then counted the number of males based on this distinction. Second, we used the more widely accepted technique of discriminant function analysis (DFA) to identify individual male cuckoos, and compared the correct rate of classifying individuals between the two analytical methods. Results: Similarity of paired calls from the same male was significantly higher than from different males. Under a relatively broad threshold interval, we achieved a high ( > 90%) correct rate to distinguish calls and an accurate estimate of male numbers. Based on banded males (n=3), we found the similarity of paired calls from different days was lower when compared with paired calls from the same day, but this change did not obscure individual identification, as similarity values of paired calls from different days were still larger than the threshold used to distinguish calls from the same or different males. DFA also yielded a high rate (91.9%) of correct classification of individuals. Conclusions: Our study suggests that identifying individual vocalizations can form the basis of an appropriate survey method for counting male cuckoos within a population, provided the performance of different analytical techniques are compared

Predicting a small molecule-kinase interaction map: A machine learning approach

<p>Abstract</p> <p>Background</p> <p>We present a machine learning approach to the problem of protein ligand interaction prediction. We focus on a set of binding data obtained from 113 different protein kinases and 20 inhibitors. It was attained through ATP site-dependent binding competition assays and constitutes the first available dataset of this kind. We extract information about the investigated molecules from various data sources to obtain an informative set of features.</p> <p>Results</p> <p>A Support Vector Machine (SVM) as well as a decision tree algorithm (C5/See5) is used to learn models based on the available features which in turn can be used for the classification of new kinase-inhibitor pair test instances. We evaluate our approach using different feature sets and parameter settings for the employed classifiers. Moreover, the paper introduces a new way of evaluating predictions in such a setting, where different amounts of information about the binding partners can be assumed to be available for training. Results on an external test set are also provided.</p> <p>Conclusions</p> <p>In most of the cases, the presented approach clearly outperforms the baseline methods used for comparison. Experimental results indicate that the applied machine learning methods are able to detect a signal in the data and predict binding affinity to some extent. For SVMs, the binding prediction can be improved significantly by using features that describe the active site of a kinase. For C5, besides diversity in the feature set, alignment scores of conserved regions turned out to be very useful.</p

A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt–TSC2-mTOR signaling

Nanoparticles are now emerging as a novel class of autophagy activators. Functionalized single-walled carbon nanotubes (f-SWCNTs) are valuable nanomaterials in many industries. This article is designed to assess the autophagic response for f-SWCNTs exposure in vitro and in vivo. A few types of f-SWCNTs were screened in human lung adenocarcinoma A549 cells for the autophagic response and related pathways in vitro. Formation of autophagosomes and LC3-II upregulation were confirmed on the basis of electron microscopy and LC3 western blotting for COOH-CNT, but not for PABS-CNT and PEG-CNT. MTT assay showed marked increase in cell viability, when COOH-CNT was added to cells in the presence of autophagy inhibitor 3MA, ATG6 or TSC2 siRNA. Consistent with the involvement of the Akt–TSC1/2–mTOR pathway, the phosphorylation levels of mTOR, mTOR's substrate S6 and Akt were shown significantly decreased in A549 cells on treatment with COOH-CNT using western blotting. What's more, autophagy inhibitor 3MA significantly reduced the lung edema in vivo. In a word, COOH-CNT induced autophagic cell death in A549 cells through the AKT–TSC2–mTOR pathway and caused acute lung injury in vivo. Inhibition of autophagy significantly reduced COOH-CNT-induced autophagic cell death and ameliorated acute lung injury in mice, suggesting a potential remedy to address the growing concerns on the safety of nanomaterials