Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study

<p>Abstract</p> <p>Background</p> <p>During inflammation, immune cells accumulate in damaged areas and release pro-inflammatory cytokines and neurotrophins. Brain-derived neurotrophic factor (BDNF) plays a neuromodulatory role in spinal cord dorsal horn via the post-synaptic tyrosine protein kinase B (trkB) receptor to facilitate pain transmission. However, the precise role of BDNF and trkB receptor in the primary sensory neurons of dorsal root ganglia (DRG) during inflammation remains to be clarified. The aim of this study was to investigate whether and how BDNF-trkB signaling in the DRG is involved in the process of inflammatory pain.</p> <p>Methods</p> <p>We used complete Freund's adjuvant- (CFA-) induced and tumor necrosis factor-α- (TNF-α-) induced inflammation in rat hindpaw as animal models of inflammatory pain. Quantification of protein and/or mRNA levels of pain mediators was performed in separate lumbar L3-L5 DRGs. The cellular mechanism of TNF-α-induced BDNF and/or trkB receptor expression was examined in primary DRG cultures collected from pooled L1-L6 DRGs. Calcitonin gene-related peptide (CGRP), BDNF and substance P release were also evaluated by enzyme immunoassay.</p> <p>Results</p> <p>CFA injection into rat hindpaw resulted in mechanical hyperalgesia and significant increases in levels of TNF-α in the inflamed tissues, along with enhancement of BDNF and trkB receptor as well as the pain mediators CGRP and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in DRG. Direct injection of TNF-α into rat hindpaw resulted in similar effects with retrograde transport of TNF-α along the saphenous nerve to DRG during CFA-induced inflammation. Primary DRG cultures chronically treated with TNF-α showed significant enhancement of mRNA and protein levels of BDNF and trkB receptor, BDNF release and trkB-induced phospho-ERK1/2 signal. Moreover, CGRP and substance P release were enhanced in DRG cultures after chronic TNF-α treatment or acute BDNF stimulation. In addition, we found that BDNF up-regulated trkB expression in DRG cultures.</p> <p>Conclusions</p> <p>Based on our current experimental results, we conclude that inflammation and TNF-α up-regulate the BDNF-trkB system in DRG. This phenomenon suggests that up-regulation of BDNF in DRG may, in addition to its post-synaptic effect in spinal dorsal horn, act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission, thereby contributing to the development of hyperalgesia.</p

Magmatic record of India-Asia collision

This work was financially co-supported by Chinese Academy of Sciences (XDB03010301) and other Chinese funding agencies (Project 973: 2011CB403102 and 2015CB452604; NSFC projects: 41225006, 41273044, and 41472061).New geochronological and geochemical data on magmatic activity from the India-Asia collision zone enables recognition of a distinct magmatic flare-up event that we ascribe to slab breakoff. This tie-point in the collisional record can be used to back-date to the time of initial impingement of the Indian continent with the Asian margin. Continental arc magmatism in southern Tibet during 80-40 Ma migrated from south to north and then back to south with significant mantle input at 70-43 Ma. A pronounced flare up in magmatic intensity (including ignimbrite and mafic rock) at ca. 52-51 Ma corresponds to a sudden decrease in the India-Asia convergence rate. Geological and geochemical data are consistent with mantle input controlled by slab rollback from ca. 70 Ma and slab breakoff at ca. 53 Ma. We propose that the slowdown of the Indian plate at ca. 51 Ma is largely the consequence of slab breakoff of the subducting Neo-Tethyan oceanic lithosphere, rather than the onset of the India-Asia collision as traditionally interpreted, implying that the initial India-Asia collision commenced earlier, likely at ca. 55 Ma.Publisher PDFPeer reviewe

A Retrospective Cohort Study Comparing Stroke Recurrence Rate in Ischemic Stroke Patients With and Without Acupuncture Treatment.

Little was known about the effects of acupuncture on stroke recurrence. The aim of this study is to investigate whether ischemic stroke patients receiving acupuncture treatment have a decreased risk of stroke recurrence. A retrospective cohort study of 30,058 newly diagnosed cases of ischemic stroke in 2000 to 2004 was conducted based on the claims of Taiwan National Health Insurance Research Database. The use of acupuncture treatment and stroke recurrence were identified during the follow-up period from 2000 to 2009. This study compared the risk of stroke recurrence between ischemic stroke cohorts with and without acupuncture treatment by calculating adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acupuncture associated with stroke recurrence in the Cox proportional hazard model. The stroke recurrence rate per 1000 person-years decreased from 71.4 without to 69.9 with acupuncture treatment (P &lt; 0.001). Acupuncture treatment was associated with reduced risk of stroke recurrence (HR 0.88; 95% CI 0.84-0.91). The acupuncture effect was noted in patients with or without medical treatment for stroke prevention but its impact decreased with aging of stroke patients. Compared with stroke patients without acupuncture treatment and medication therapy, the hazard ratios of stroke recurrence for those had medication therapy only, acupuncture only, and both were 0.42 (95% CI 0.38-0.46), 0.50 (95% CI 0.43-0.57), and 0.39 (95% CI 0.35-0.43), respectively. This study raises the possibility that acupuncture might be effective in lowering stroke recurrence rate even in those on medications for stroke prevention. Results suggest the need of prospective sham-controlled and randomized trials to establish the efficacy of acupuncture in preventing stroke

Magnesium isotopic composition of the oceanic mantle and oceanic Mg cycling

© The Author(s), 2017. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 206 (2017): 151-165, doi:10.1016/j.gca.2017.02.016.To constrain the Mg isotopic composition of the oceanic mantle, investigate Mg isotope fractionation of abyssal peridotites during seafloor alteration, and assess Mg budget in the oceans, a suite of 32 abyssal peridotite samples from the Gakkel Ridge and Southwest Indian Ridge (SWIR) was, for the first time, selected for high-precision Mg isotope analyses. Although most of these samples are extensively altered, largely by serpentinization and weathering, primary olivine, diopside and enstatite grains are preserved in some samples. Olivine grains from the least altered samples have δ26Mg varying from −0.30 to −0.12‰ (n = 7), whereas enstatite and diopside have δ26Mg varying from −0.27 to −0.16‰ (n = 7), and from −0.23 to −0.09‰ (n = 6), respectively. Whole-rock δ26Mg values range from −0.24 to 0.03‰ with an average of −0.12 ± 0.13‰ (2SD, n = 32). Strongly serpentinized peridotites have lower average δ26Mg values (δ26Mg = −0.19 ± 0.07‰, 2SD, n = 7) than weathering-dominated ones (δ26Mg = −0.10 ± 0.12‰, 2SD, n = 25). Calculated Mg isotopic compositions of fresh mantle peridotites vary from −0.29 to −0.13‰, beyond the previously reported range of the subcontinental lithospheric mantle (−0.25 ± 0.04‰) and the analytical uncertainty (±0.07‰, 2SD). Our study therefore indicates that the oceanic mantle may have similar but slightly heterogeneous Mg isotopic compositions to that of subcontinental lithospheric mantle. Secondary serpentinization does not fractionate Mg isotopes of abyssal peridotites, whereas low-T weathering and formation of clay can result in the enrichment of heavy Mg isotopes in abyssal peridotites. This study also demonstrates that fluid-rock interaction does not necessarily produce rocks with intermediate Mg isotopic compositions. Magnesium isotopes of the rocks thereafter are dependent on the secondary minerals formed. We also conclude that the release of light Mg isotopes into the ocean during alteration of abyssal peridotites can be an important influx of Mg for the seawater Mg budget. Abyssal peridotites with a heavy Mg isotopic signature can be recycled into the mantle in subduction zones and may thus result in heterogeneous Mg isotopic compositions of the oceanic mantle and heavy Mg isotopic compositions of arc magmas.This study was supported by grants from the National Science Foundation of China (grants 41473038 and 41503010), China Postdoctoral Science Foundation (2015M570145), National Science Foundation (EAR-1056713 and EAR-1340160) and project MOST104 -2745-M-002-001-ASP granted to SLC. Partial support for HJBD was provided by the US National Science Foundation (OCE-1434452)

Long run credit risk diversification: empirical decomposition of corporate bond spreads

Following the reduced-form models of Duffee (1999) and Jarrow, Lando and Yu (2003), this study investigates the risk diversification issue of corporate bond portfolios. Considering especially long run market behavior, our empirical decomposition of corporate bond yield spreads indicates that the idiosyncratic component serves as a good vehicle for risk diversification. Moreover, the diosyncratic spread provides significant inferences about observed conditional corporate bond default rate, while full spread does not. Applying an affine model from Duffie and Singleton (1999), we find that the idiosyncratic credit spreads do not respond empirically to Treasury yields, unlike what is suggested in the structural model of Longstaff and Schwartz (1995) and literatures that follow. Systematic credit spreads are however positively related to Treasury yields in the long-run, but negatively so in the short run, suggesting the validity of both the tax and the option hypotheses. A long-run and optimal decomposition scheme yields an idiosyncratic credit spread measure at a median of 60 b.p. for the Baa index and is specifically compatible with Duffee’s model. It is insensitive to interest rate in the short-run, but would rise slightly with a positive shock in the long run at a rate of one to a hundred. Our findings in the study contribute to the risk practice of bond portfolio diversification