Neuroglobin, a Novel Target for Endogenous Neuroprotection against Stroke and Neurodegenerative Disorders

Brain neurons and tissues respond to sublethal injury by activating endogenous protective pathways. Recently, following the failure of a large number of clinical trials for protective strategies against stroke that aim to inhibit a specific ischemia response pathway, endogenous neuroprotection has emerged as a more promising and hopeful strategy for development of therapeutics against stroke and neurodegenerative disorders. Neuroglobin (Ngb) is an oxygen-binding globin protein that is highly and specifically expressed in brain neurons. Accumulating evidence have clearly demonstrated that Ngb is an endogenous neuroprotective molecule against hypoxic/ischemic and oxidative stress-related insults in cultured neurons and animals, as well as neurodegenerative disorders such as Alzheimer’s disease, thus any pharmacological strategy that can up-regulate endogenous Ngb expression may lead to novel therapeutics against these brain disorders. In this review, we summarize recent studies about the biological function, regulation of gene expression, and neuroprotective mechanisms of Ngb. Furthermore, strategies for identification of chemical compounds that can up-regulate endogenous Ngb expression for neuroprotection against stroke and neurodegenerative disorders are discussed

Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Xu, X., Li, G., Li, C., Zhang, J., Wang, Q., Simmons, D. K., Chen, X., Wijesena, N., Zhu, W., Wang, Z., Wang, Z., Ju, B., Ci, W., Lu, X., Yu, D., Wang, Q., Aluru, N., Oliveri, P., Zhang, Y. E., Martindale, M. Q., & Liu, J. Evolutionary transition between invertebrates and vertebrates via methylation reprogramming in embryogenesis. National Science Review, 6(5), (2019):993-1003, doi:10.1093/nsr/nwz064.Major evolutionary transitions are enigmas, and the most notable enigma is between invertebrates and vertebrates, with numerous spectacular innovations. To search for the molecular connections involved, we asked whether global epigenetic changes may offer a clue by surveying the inheritance and reprogramming of parental DNA methylation across metazoans. We focused on gametes and early embryos, where the methylomes are known to evolve divergently between fish and mammals. Here, we find that methylome reprogramming during embryogenesis occurs neither in pre-bilaterians such as cnidarians nor in protostomes such as insects, but clearly presents in deuterostomes such as echinoderms and invertebrate chordates, and then becomes more evident in vertebrates. Functional association analysis suggests that DNA methylation reprogramming is associated with development, reproduction and adaptive immunity for vertebrates, but not for invertebrates. Interestingly, the single HOX cluster of invertebrates maintains unmethylated status in all stages examined. In contrast, the multiple HOX clusters show dramatic dynamics of DNA methylation during vertebrate embryogenesis. Notably, the methylation dynamics of HOX clusters are associated with their spatiotemporal expression in mammals. Our study reveals that DNA methylation reprogramming has evolved dramatically during animal evolution, especially after the evolutionary transitions from invertebrates to vertebrates, and then to mammals.This work was supported by the National Key Research and Development Program of China (2018YFC1003303), the Strategic Priority Research Program of the CAS (XDB13040200), the National Natural Science Foundation of China (91519306, 31425015), the Youth Innovation Promotion Association of the CAS and the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SMC016)

Research on Traffic Signal Timing Method Based on Ant Colony Algorithm and Fuzzy Control Theory

The number of private cars has a blowout growth with the development of economics, which leads to the existing limited traffic resources cannot meet the normal traffic demand. The emergence of intelligent traffic has improved this phenomenon. Using intelligent traffic technology to conduct intersection vehicles can alleviate the congestion effectively. Traffic signal timing method plays an important role in intelligent traffic research. An independent intersection dynamic timing method combined with fuzzy control theory and improved ant colony algorithm is proposed in this paper. According to the characteristics of traffic flow distribution, the timing period is obtained with the improved webster algorithm. Through the optimal solution obtained by ant colony algorithm and the added delay of traffic signal calculated by fuzzy control method, the dynamic timing period of the traffic signal is obtained. The validity of the proposed method is proved by comparing with the original time period and the traditional algorithm

Neuroglobin-overexpression reduces traumatic brain lesion size in mice

Background: Accumulating evidence has demonstrated that over-expression of Neuroglobin (Ngb) is neuroprotective against hypoxic/ischemic brain injuries. In this study we tested the neuroprotective effects of Ngb over-expression against traumatic brain injury (TBI) in mice. Results: Both Ngb over-expression transgenic (Ngb-Tg) and wild-type (WT) control mice were subjected to TBI induced by a controlled cortical impact (CCI) device. TBI significantly increased Ngb expression in the brains of both WT and Ngb-Tg mice, but Ngb-Tg mice had significantly higher Ngb protein levels at the pre-injury baseline and post-TBI. Production of oxidative tissue damage biomarker 3NT in the brain was significantly reduced in Ngb-Tg mice compared to WT controls at 6 hours after TBI. The traumatic brain lesion volume was significantly reduced in Ngb Tg mice compared to WT mice at 3 weeks after TBI; however, there were no significant differences in the recovery of sensorimotor and spatial memory functional deficits between Ngb-Tg and WT control mice for up to 3 weeks after TBI. Conclusion: Ngb over-expression reduced traumatic lesion volume, which might partially be achieved by decreasing oxidative stress

On the topological surface states of the intrinsic magnetic topological insulator Mn-Bi-Te family

We review recent progress in the electronic structure study of intrinsic magnetic topological insulators (MnBi$_2$Te$_4$)(Bi$_2$Te$_3$)$_n$ ($n=0,1,2,3$) family. Specifically, we focus on the ubiquitously (nearly) gapless behavior of the topological surface state Dirac cone observed by photoemission spectroscopy, even though a large Dirac gap is expected because of surface ferromagnetic order. The dichotomy between experiment and theory concerning this gap behavior is perhaps the most critical and puzzling question in this frontier. We discuss various proposals accounting for the lack of magnetic effect on the topological surface state Dirac cone, which are mainly categorized into two pictures, magnetic reconfiguration, and topological surface state redistribution. Band engineering towards opening a magnetic gap of topological surface states provides great opportunities to realize quantized topological transport and axion electrodynamics at higher temperatures

Efficacy and safety of olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized controlled trials

BackgroundOlaparib has been proven for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This meta-analysis aims to comprehensively evaluate the efficacy and safety of the combination of olaparib and abiraterone in patients with mCRPC.MethodsThe literature in PubMed, Embase, and Cochrane Library up until April 27, 2023, was systematically searched. In the studies included in this meta-analysis, olaparib combined with abiraterone was compared with abiraterone combined with placebo.ResultsTwo randomized controlled trials involving a total of 938 patients were included. Analysis indicated that olaparib combined with abiraterone significantly prolonged radiographic progression-free survival (rPFS: relative risk [RR] 0.66, 95% confidence interval [CI] 0.55–0.79), time to secondary progression or death (PFS2: hazard ratio [HR] 0.72, 95% CI 0.56–0.93), time to first subsequent therapy or death (TFST: HR 0.75, 95% CI 0.63–0.89), time to second subsequent therapy or death (TSST: HR 0.73, 95% CI 0.58–0.93), and confirmed prostate-specific antigen (PSA) response (RR 1.14, 95% CI 1.05–1.24). However, no statistically significant differences were found in the overall survival (OS: HR 0.87 95% CI 0.70–1.09), objective response rate (ORR: RR 0.97, 95% CI 0.70–1.33), and incidence of total adverse events (RR 1.07, 95% CI 0.94–1.22). A notable detail that the combination of olaparib and abiraterone was associated with an increased incidence of high-grade anemia (RR 7.47, 95% CI 1.36–40.88).ConclusionOlaparib combined with abiraterone is effective for patients with mCRPC. However, combination therapy has treatment-related adverse events compared with monotherapy, and this could be improved in future treatment management.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432287

Thrombospondin-1 Gene Deficiency Worsens the Neurological Outcomes of Traumatic Brain Injury in Mice

Background: Thrombospondin-1 (TSP-1) is an extracellular matrix protein that plays multiple physiological and pathophysiological roles in the brain. Experimental reports suggest that TSP-1 may have an adverse role in neuronal function recovery under certain injury conditions. However, the roles of TSP-1 in traumatic brain injury (TBI) have not been elucidated. In this study we for the first time investigated the roles of TSP-1 in a controlled cortical impact (CCI) model of TBI in TSP-1 knockout (TSP-1 KO) and wild type (WT) mice. Methods: We examined blood brain-barrier (BBB) damage using at 1 day post-TBI by measuring Evans Blue leakage, and neurological functional recovery at 3 weeks post-TBI by measuring neurological severity score (NSS), wire gripping, corner test and Morris Water Maze (MWM). Mechanistically, we quantified pro-angiogenic biomarkers including cerebral vessel density, vascular endothelial growth factors (VEGF) and angiopoietin-1 (Ang-1) protein expression, synaptic biomarker synaptophysin, and synaptogenesis marker brain-derived neurotrophic factor (BDNF) protein expression in contralateral and ipsilateral (peri-lesion) cortex at 21 days after TBI using immunohistochemistry and Western Blot. Results: TSP-1 is upregulated at early phase of TBI in WT mice. Compared to WT mice, TSP-1 KO (1) significantly worsened TBI-induced BBB leakage at 1 day after TBI; (2) had similar lesion size as WT mice at 3 weeks after TBI; (3) exhibited a significantly worse neurological deficits in motor and cognitive functions; (4) had no significant difference in cerebral vessel density, but significant increase of VEGF and Ang-1 protein expressions in peri-lesion cortex; (5) significantly increased BDNF but not synaptophysin protein level in peri-lesion cortex compared to sham, but both synaptophysin and BDNF expressions were significantly decreased in contralateral cortex compared to WT. Conclusion: Our results suggest that TSP-1 may be beneficial for maintaining BBB integrity in the early phase and functional recovery in late phase after TBI. The molecular mechanisms of TSP-1 in early BBB pathophysiology, and long-term neurological function recovery after TBI need to be further investigated

Gapless surface Dirac cone in antiferromagnetic topological insulator MnBi2_2Te4_4

The recent discovered antiferromagnetic topological insulators in Mn-Bi-Te family with intrinsic magnetic ordering have rapidly drawn broad interest since its cleaved surface state is believed to be gapped, hosting the unprecedented axion states with half-integer quantum Hall effect. Here, however, we show unambiguously by using high-resolution angle-resolved photoemission spectroscopy that a gapless Dirac cone at the (0001) surface of MnBi$_2$Te$_4$ exists between the bulk band gap. Such unexpected surface state remains unchanged across the bulk N\'eel temperature, and is even robust against severe surface degradation, indicating additional topological protection. Through symmetry analysis and $\textit{ab}$-$\textit{initio}$ calculations we consider different types of surface reconstruction of the magnetic moments as possible origins giving rise to such linear dispersion. Our results reveal that the intrinsic magnetic topological insulator hosts a rich platform to realize various topological phases such as topological crystalline insulator and time-reversal-preserved topological insulator, by tuning the magnetic configurations.Comment: 9 pages, 4 figures. To appear in Phys. Rev. X. See Version 1 for the supplementary fil