Heme oxygenase-1 plays a pro-life role in experimental brain stem death via nitric oxide synthase I/protein kinase G signaling at rostral ventrolateral medulla

<p>Abstract</p> <p>Background</p> <p>Despite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. A suitable neural substrate for mechanistic delineation on brain stem death resides in the rostral ventrolateral medulla (RVLM) because it is the origin of a life-and-death signal that sequentially increases (pro-life) and decreases (pro-death) to reflect the advancing central cardiovascular regulatory dysfunction during the progression towards brain stem death in critically ill patients. The present study evaluated the hypothesis that heme oxygnase-1 (HO-1) may play a pro-life role as an interposing signal between hypoxia-inducible factor-1 (HIF-1) and nitric oxide synthase I (NOS I)/protein kinase G (PKG) cascade in RVLM, which sustains central cardiovascular regulatory functions during brain stem death.</p> <p>Methods</p> <p>We performed cardiovascular, pharmacological, biochemical and confocal microscopy experiments in conjunction with an experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of adult male Sprague-Dawley rats.</p> <p>Results</p> <p>Western blot analysis coupled with laser scanning confocal microscopy revealed that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons occurred preferentially during the pro-life phase of experimental brain stem death and was antagonized by immunoneutralization of HIF-1α or HIF-1β in RVLM. On the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested insignificant changes during both phases. Furthermore, immunoneutralization of HO-1 or knockdown of <it>ho-1 </it>gene in RVLM blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS II/peroxynitrite cascade in RVLM.</p> <p>Conclusions</p> <p>We conclude that transcriptional upregulation of HO-1 on activation by HIF-1 in RVLM plays a preferential pro-life role by sustaining central cardiovascular regulatory functions during brain stem death via upregulation of NOS I/PKG signaling pathway. Our results further showed that the pro-dead NOS II/peroxynitrite cascade in RVLM is not included in this repertoire of cellular events.</p

Abnormal brain spontaneous activity in major depressive disorder adolescents with non-suicidal self injury and its changes after sertraline therapy

BackgroundNon-suicidal self-injury (NSSI) commonly occurs among adolescents with major depressive disorder (MDD), causing adverse effects on the physical and mental health of the patients. However, the underlying neurobiological mechanism of NSSI in adolescents with MDD (nsMDDs) remains unclear, and there are still challenges in the treatment. Studies have suggested that sertraline administration could be an effective way for treatment.MethodsTo verify the effectiveness and to explore the neurobiological processes, we treated a group of adolescents with nsMDDs with sertraline in this study. The brain spontaneous activity alteration was then investigated in fifteen unmedicated first-episode adolescent nsMDDs versus twenty-two healthy controls through the resting-state functional magnetic resonance imaging. Besides the baseline scanning for all participants, the nsMDDs group was scanned again after eight weeks of sertraline therapy to examine the changes after treatment.ResultsAt pre-treatment, whole brain analysis of mean amplitude of low-frequency fluctuation (mALFF) was performed to examine the neuronal spontaneous activity alteration, and increased mALFF was found in the superior occipital extending to lingual gyrus in adolescent nsMDDs compared with controls. Meanwhile, decreased mALFF was found in the medial superior frontal in adolescent nsMDDs compared with controls. Compared with the pre-treatment, the nsMDDs group was found to have a trend of, respectively, decreased and increased functional neuronal activity at the two brain areas after treatment through the region of interest analysis. Further, whole brain comparison of mALFF at pre-treatment and post-treatment showed significantly decreased spontaneous activity in the orbital middle frontal and lingual gyrus in adolescent nsMDDs after treatment. Also, depression severity was significantly decreased after treatment.ConclusionThe abnormal functional neuronal activity found at frontal and occipital cortex implied cognitive and affective disturbances in adolescent nsMDDs. The trend of upregulation of frontal neuronal activity and downregulation of occipital neuronal activity after sertraline treatment indicated that the therapy could be effective in regulating the abnormality. Notably, the significantly decreased neuronal activity in the decision related orbital middle frontal and anxiety-depression related lingual gyrus could be suggestive of reduced NSSI in adolescent MDD after therapy

Calculation of the Chiral Lagrangian Coefficients from the Underlying Theory of QCD: A Simple Approach

We calculate the coefficients in the chiral Lagrangian approximately from QCD based on a previous study of deriving the chiral Lagrangian from the first principles of QCD in which the chiral Lagrangian coefficients are defined in terms of certain Green's functions in QCD. We first show that, in the large N(c)-limit, the anomaly part contributions to the coefficients are exactly cancelled by certain terms in the normal part contributions, and the final results of the coefficients only concern the remaining normal part contributions depending on QCD interactions. We then do the calculation in a simple approach with the approximations of taking the large-N(c) limit, the leading order in dynamical perturbation theory, and the improved ladder approximation, thereby the relevant Green's functions are expressed in terms of the quark self energy. By solving the Schwinger-Dyson equation for the quark self energy, we obtain the approximate QCD predicted coefficients and the quark condensate which are consistent with the experimental values.Comment: Further typos corrected, to appear in Phys. Rev.

Genetic Diversity, Inbreeding Level, and Genetic Load in Endangered Snub-Nosed Monkeys (Rhinopithecus)

The snub-nosed monkey genus (Rhinopithecus) comprises five closely related species (R. avunculus, R. bieti, R. brelichi, R. roxellana, and R. strykeri). All are among the world's rarest and most endangered primates. However, the genomic impact associated with their population decline remains unknown. We analyzed population genomic data of all five snub-nosed monkey species to assess their genetic diversity, inbreeding level, and genetic load. For R. roxellana, R. bieti, and R. strykeri, population size is positively correlated with genetic diversity and negatively correlated with levels of inbreeding. Other species, however, which possess small population sizes, such as R. brelichi and R. avunculus, show high levels of genetic diversity and low levels of genomic inbreeding. Similarly, in the three populations of R. roxellana, the Shennongjia population, which possesses the lowest population size, displays a higher level of genetic diversity and lower level of genomic inbreeding. These findings suggest that although R. brelichi and R. avunculus and the Shennongjia population might be at risk, it possess significant genetic diversity and could thus help strengthen their long-term survival potential. Intriguingly, R. roxellana with large population size possess high genetic diversity and low level of genetic load, but they show the highest recent inbreeding level compared with the other snub-nosed monkeys. This suggests that, despite its large population size, R. roxellana has likely been experiencing recent inbreeding, which has not yet affected its mutational load and fitness. Analyses of homozygous-derived deleterious mutations identified in all snub-nosed monkey species indicate that these mutations are affecting immune, especially in smaller population sizes, indicating that the long-term consequences of inbreeding may be resulting in an overall reduction of immune capability in the snub-nosed monkeys, which could provide a dramatic effect on their long-term survival prospects. Altogether, our study provides valuable information concerning the genomic impact of population decline of the snub-nosed monkeys. We revealed multiple counterintuitive and unexpected patterns of genetic diversity in small and large population, which will be essential for conservation management of these endangered species

Investigation of the Anti-Inflammatory Activity of Fusaproliferin Analogues Guided by Transcriptome Analysis

Background: Excessive inflammation results in severe tissue damage as well as serious acute or chronic disorders, and extensive research has focused on finding new anti-inflammatory hit compounds with safety and efficacy profiles from natural products. As promising therapeutic entities for the treatment of inflammation-related diseases, fusaproliferin and its analogs have attracted great interest. However, the underlying anti-inflammatory mechanism is still poorly understood and deserves to be further investigated.Methods: For the estimation of the anti-inflammatory activity of fusaproliferin (1) and its analogs (2-4)in vitro and in vivo, lipopolysaccharide (LPS)-induced RAW264.7 macrophages and zebrafish embryos were employed. Then, transcriptome analysis was applied to guide subsequent western blot analysis of critical proteins in related signaling pathways. Surface plasmon resonance assays (SPR) combined with molecular docking analyses were finally applied to evaluate the affinity interactions between 1-4 and TLR4 and provide a possible interpretation of the downregulation of related signaling pathways.Results: 1-4 significantly attenuated the production of inflammatory messengers, including nitric oxide (NO), reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the ability of compound 1 to reverse LPS stimulation and the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPKs) signaling pathways contribute to the anti-inflammatory process. Experimental verification at the protein level revealed that 1 can inhibit the activation of inhibitor of NF-κB kinase (IKK), degradation of inhibitor of NF-κB (IκB), and phosphorylation of NF-κB and reduce nuclear translocation of NF-κB. 1 also decreased the phosphorylation of MAPKs, including p38, extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK). SPR assays and molecular docking results indicated that 1-4 exhibited affinity for the TLR4 protein with KD values of 23.5–29.3 μM.Conclusion: Fusaproliferin and its analogs can be hit compounds for the treatment of inflammation-associated diseases

A Wireless Sensor Network Based Personnel Positioning Scheme in Coal Mines with Blind Areas

This paper proposes a novel personnel positioning scheme for a tunnel network with blind areas, which compared with most existing schemes offers both low-cost and high-precision. Based on the data models of tunnel networks, measurement networks and mobile miners, the global positioning method is divided into four steps: (1) calculate the real time personnel location in local areas using a location engine, and send it to the upper computer through the gateway; (2) correct any localization errors resulting from the underground tunnel environmental interference; (3) determine the global three-dimensional position by coordinate transformation; (4) estimate the personnel locations in the blind areas. A prototype system constructed to verify the positioning performance shows that the proposed positioning system has good reliability, scalability, and positioning performance. In particular, the static localization error of the positioning system is less than 2.4 m in the underground tunnel environment and the moving estimation error is below 4.5 m in the corridor environment. The system was operated continuously over three months without any failures

Look, the World is Watching How We Treat Migrants! The Making of the Anti-Trafficking Legislation during the Ma Administration

Employing the spiral model, this research analyses how anti-human trafficking legislation was promulgated during the Ma Ying-jeou (Ma Yingjiu) presidency. This research found that the gov- ernment of Taiwan was just as accountable for the violation of mi- grants’ human rights as the exploitive placement agencies and abusive employers. This research argues that, given its reliance on the United States for political and security support, Taiwan has made great ef- forts to improve its human rights records and meet US standards for protecting human rights. The reform was a result of multilevel inputs, including US pressure and collaboration between transnational and domestic advocacy groups. A major contribution of this research is to challenge the belief that human rights protection is intrinsic to dem- ocracy. In the same light, this research also cautions against Taiwan’s subscription to US norms since the reform was achieved at the cost of stereotyping trafficking victimhood, legitimising state surveillance, and further marginalising sex workers

Measurements of the Mass and Full-Width of the ηc\eta_c Meson

In a sample of 58 million $J/\psi$ events collected with the BES II detector, the process J/$\psi\to\gamma\eta_c$ is observed in five different decay channels: $\gamma K^+K^-\pi^+\pi^-$, $\gamma\pi^+\pi^-\pi^+\pi^-$, $\gamma K^\pm K^0_S \pi^\mp$ (with $K^0_S\to\pi^+\pi^-$), $\gamma \phi\phi$ (with $\phi\to K^+K^-$) and $\gamma p\bar{p}$. From a combined fit of all five channels, we determine the mass and full-width of $\eta_c$ to be $m_{\eta_c}=2977.5\pm1.0 ({stat.})\pm1.2 ({syst.})$ MeV/$c^2$ and $\Gamma_{\eta_c} = 17.0\pm3.7 ({stat.})\pm7.4 ({syst.})$ MeV/$c^2$.Comment: 9 pages, 2 figures and 4 table. Submitted to Phys. Lett.

\psi(2S) Decays into \J plus Two Photons

Using \gamma \gamma J/\psi, J/\psi \ra e^+ e^- and $\mu^+ \mu^-$ events from a sample of $14.0\times 10^6$ \psip decays collected with the BESII detector, the branching fractions for \psip\ra \pi^0\J, \eta\J, and \psi(2S)\ar\gamma\chi_{c1},\gamma\chi_{c2}\ar\gamma\gamma\jpsi are measured to be B(\psip\ra \pi^0\J) = (1.43\pm0.14\pm0.13)\times 10^{-3}, B(\psip\ra \eta\J) = (2.98\pm0.09\pm0.23)%, B(\psi(2S)\ar\gamma\chi_{c1}\ar\gamma\gamma\jpsi) = (2.81\pm0.05\pm 0.23)%, and B(\psi(2S)\ar\gamma\chi_{c2}\ar\gamma\gamma\jpsi) = (1.62\pm0.04\pm 0.12)%.Comment: 7 pages, 6 figures. submitted to Phys. Rev.