452 research outputs found
The role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy.
Neonates can develop hypoxic-ischaemic encephalopathy (HIE) due to lack of blood supply or oxygen, resulting in a major cause of death and disability among term newborns. However, current definitive treatment of therapeutic hypothermia, will only benefit one out of nine babies. Furthermore, the mechanisms of HIE and therapeutic hypothermia are not fully understood. Recently, microRNAs (miRNAs) have become of interest to many researchers due to their important role in post-transcriptional control and deep evolutionary history. Despite this, role of miRNAs in newborns with HIE remains largely unknown due to limited research in this field. Therefore, this review aims to understand the role of miRNAs in normal brain development and HIE pathophysiology with reliance on extrapolated data from other diseases, ages and species due to current limited data. This will provide us with an overview of how miRNAs in normal brain development changes after HIE. Furthermore, it will indicate how miRNAs are affected specifically or globally by the various pathophysiological events. In addition, we discuss about how drugs and commercially available agents can specifically target certain miRNAs as a mechanism of action and potential safety issue with off-target effects. Improving our understanding of the role of miRNAs on the cellular response after HIE would enhance the success of effective diagnosis, prognosis, and treatment of newborns with HIE
A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury
This work was supported by Chang GungMemorialHospital, Taiwan CMRPG3A1051–1054to Z.-H.L., CMDRP and Barts and the London Charity to P.K.Y. and A.T.M.-T., and the Nathalie Rose Barr PhD Studentship ISRT to L.A. andJ.V.P
Newborns with Favourable Outcomes after Perinatal Asphyxia Have Upregulated Glucose Metabolism-Related Proteins in Plasma.
Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality globally. Although mild therapeutic hypothermia (TH) may improve outcomes in selected babies, the mechanism of action is not fully understood. A proteomics discovery study was carried out to analyse proteins in the plasma of newborns with HIE. Proteomic analysis of plasma from 22 newborns with moderate-severe HIE that had initially undergone TH, and relative controls including 10 newborns with mild HIE who did not warrant TH and also cord blood from 10 normal births (non-HIE) were carried out using the isobaric Tandem Mass Tag (TMT®) 10plexTM labelling with tandem mass spectrometry. A total of 7818 unique peptides were identified in all TMT10plexTM samples, translating to 3457 peptides representing 405 proteins, after applying stringent filter criteria. Apart from the unique protein signature from normal cord blood, unsupervised analysis revealed several significantly regulated proteins in the TH-treated moderate-severe HIE group. GO annotation and functional clustering revealed various proteins associated with glucose metabolism: the enzymes fructose-bisphosphate aldolase A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, phosphoglycerate kinase 1, and pyruvate kinase PKM were upregulated in newborns with favourable (sHIE+) outcomes compared to newborns with unfavourable (sHIE-) outcomes. Those with favourable outcomes had normal MR imaging or mild abnormalities not predictive of adverse outcomes. However, in comparison to mild HIE and the sHIE- groups, the sHIE+ group had the additional glucose metabolism-related enzymes upregulated, including triosephosphate isomerase, α-enolase, 6-phosphogluconate dehydrogenase, transaldolase, and mitochondrial glutathione reductase. In conclusion, our plasma proteomic study demonstrates that TH-treated newborns with favourable outcomes have an upregulation in glucose metabolism. These findings may open new avenues for more effective neuroprotective therapy
Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy
Refining rodent models of spinal cord injury.
This report was produced by an Expert Working Group (EWG) consisting of UK-based researchers, veterinarians and regulators of animal experiments with specialist knowledge of the use of animal models of spinal cord injury (SCI). It aims to facilitate the implementation of the Three Rs (Replacement, Reduction and Refinement), with an emphasis on refinement. Specific animal welfare issues were identified and discussed, and practical measures proposed, with the aim of reducing animal use and suffering, reducing experimental variability, and increasing translatability within this critically important research field
Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury
Microglia are activated after spinal cord injury (SCI), but their phagocytic mechanisms and link to neuroprotection remain incompletely characterized. Docosahexaenoic acid (DHA) has been shown to have significant neuroprotective effects after hemisection and compression SCI and can directly affect microglia in these injury models. In rodent contusion SCI, we demonstrate that DHA (500 nmol/kg) administered acutely post-injury confers neuroprotection and enhances locomotor recovery, and also exerts a complex modulation of the microglial response to injury. In rodents, at 7 days after SCI, the level of phagocytosed myelin within Iba1-positive or P2Y12-positive cells was significantly lower after DHA treatment, and this occurred in parallel with an increase in intracellular miR-124 expression. Furthermore, intraspinal administration of a miR-124 inhibitor significantly reduced the DHA-induced decrease in myelin phagocytosis in mice at 7 days post-SCI. In rat spinal primary microglia cultures, DHA reduced the phagocytic response to myelin, which was associated with an increase in miR-124, but not miR-155. A similar response was observed in a microglia cell line (BV2) treated with DHA, and the effect was blocked by a miR-124 inhibitor. Furthermore, the phagocytic response of BV2 cells to stressed neurones was also reduced in the presence of DHA. In peripheral monocyte-derived macrophages, the expression of the M1, but not the M0 or M2 phenotype, was reduced by DHA, but the phagocytic activation was not altered. These findings show that DHA induces neuroprotection in contusion injury. Furthermore, the improved outcome is via a miR-124-dependent reduction in the phagocytic response of microglia.US Department of Defence CDMRP/SCIRP award (W81XWH-10-1-1040 to P.K.Y., T.B. and A.M.T.); The Barts and London Charity (to P.K.Y. and A.M.T.); Rod Flower Vacation Scholarship (to A.L.B.); International Spinal Research Trust (to J.H. and P.G.P.); Ray W. Poppleton Endowment (to P.G.P.); Chang Gung Memorial Hospital, Taiwan (CMRPG3A1051–1054 to Z.-H.L.). M.A.B. is funded by the Spanish Ministry of Economy and Competitivity (Programa Ramón y Cajal: RYC-2017-21804)
Acute Ethanol Effects on Focal Cerebral Ischemia in Nonfasted Rats
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66417/1/j.1530-0277.1997.tb03832.x.pd
Stimulation of Na<sup>+</sup>/H<sup>+</sup> Exchanger Isoform 1 Promotes Microglial Migration
Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling. © 2013 Shi et al
An interdisciplinary intervention for older Taiwanese patients after surgery for hip fracture improves health-related quality of life
Abstract Background The effects of intervention programs on health-related quality of life (HRQOL) of patients with hip fracture have not been well studied. We hypothesized that older patients with hip fracture who received our interdisciplinary intervention program would have better HRQOL than those who did not. Methods A randomized experimental design was used. Older patients with hip fracture (N = 162), 60 to 98 years old, from a medical center in northern Taiwan were randomly assigned to an experimental (n = 80) or control (n = 82) group. HRQOL was measured by the SF-36 Taiwan version at 1, 3, 6, and 12 months after discharge. Results The experimental group had significantly better overall outcomes in bodily pain (β = 9.38, p = 0.002), vitality (β = 9.40, p < 0.001), mental health (β = 8.16, p = 0.004), physical function (β = 16.01, p < 0.001), and role physical (β = 22.66, p < 0.001) than the control group at any time point during the first year after discharge. Physical-related health outcomes (physical functioning, role physical, and vitality) had larger treatment effects than emotional/mental- and social functioning-related health outcomes. Conclusions This interdisciplinary intervention program may improve health outcomes of elders with hip fracture. Our results may provide a reference for health care providers in countries using similar programs with Chinese/Taiwanese immigrant populations. Trial registration NCT01052636http://deepblue.lib.umich.edu/bitstream/2027.42/78259/1/1471-2474-11-225.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78259/2/1471-2474-11-225.pdfPeer Reviewe
Computing the Viscosity of Supercooled Liquids: Markov Network Model
The microscopic origin of glass transition, when liquid viscosity changes continuously by more than ten orders of magnitude, is challenging to explain from first principles. Here we describe the detailed derivation and implementation of a Markovian Network model to calculate the shear viscosity of deeply supercooled liquids based on numerical sampling of an atomistic energy landscape, which sheds some light on this transition. Shear stress relaxation is calculated from a master-equation description in which the system follows a transition-state pathway trajectory of hopping among local energy minima separated by activation barriers, which is in turn sampled by a metadynamics-based algorithm. Quantitative connection is established between the temperature variation of the calculated viscosity and the underlying potential energy and inherent stress landscape, showing a different landscape topography or “terrain” is needed for low-temperature viscosity (of order 10[superscript 7] Pa·s) from that associated with high-temperature viscosity (10[superscript −5] Pa·s). Within this range our results clearly indicate the crossover from an essentially Arrhenius scaling behavior at high temperatures to a low-temperature behavior that is clearly super-Arrhenius (fragile) for a Kob-Andersen model of binary liquid. Experimentally the manifestation of this crossover in atomic dynamics continues to raise questions concerning its fundamental origin. In this context this work explicitly demonstrates that a temperature-dependent “terrain” characterizing different parts of the same potential energy surface is sufficient to explain the signature behavior of vitrification, at the same time the notion of a temperature-dependent effective activation barrier is quantified.Corning IncorporatedBoston University. Center for Scientific Computing and VisualizationNational Science Foundation (U.S.) (grant DMR-1008104)National Science Foundation (U.S.) (grant DMR-0520020)United States. Air Force Office of Scientific Research (FA9550-08-1-0325
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