Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR‐127 in aged animals

Envelliment; Inflamació; MicroARNEnvejecimiento; Inflamación; MicroARNAging; Inflammation; MicroRNAIschemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke‐induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron‐specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co‐existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR‐127, that is highly neuronal, to be associated with increased cell death in the aged, LPS‐injected ischemic mice. Target prediction tools indicate that miR‐127 interacts with several basally expressed neuronal genes, and of these we verify miR‐127 binding to Psmd3. Finally, we report reduced expression of miR‐127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.This study was supported by Emil Aaltonen Foundation, Academy of Finland and Finnish Cultural Foundation

Peripheral inflammation preceeding ischemia impairs neuronal survival through mechanisms involving miR-127 in aged animals

Ischemic stroke, the third leading cause of death in the Western world, affects mainly the elderly and is strongly associated with comorbid conditions such as atherosclerosis or diabetes, which are pathologically characterized by increased inflammation and are known to influence the outcome of stroke. Stroke incidence peaks during influenza seasons, and patients suffering from infections such as pneumonia prior to stroke exhibit a worse stroke outcome. Earlier studies have shown that comorbidities aggravate the outcome of stroke, yet the mediators of this phenomenon remain obscure. Here, we show that acute peripheral inflammation aggravates stroke-induced neuronal damage and motor deficits specifically in aged mice. This is associated with increased levels of plasma proinflammatory cytokines, rather than with an increase of inflammatory mediators in the affected brain parenchyma. Nascent transcriptomics data with mature microRNA sequencing were used to identify the neuron-specific miRNome, in order to decipher dysregulated miRNAs in the brains of aged animals with stroke and co-existing inflammation. We pinpoint a previously uninvestigated miRNA in the brain, miR-127, that is highly neuronal, to be associated with increased cell death in the aged, LPS-injected ischemic mice. Target prediction tools indicate that miR-127 interacts with several basally expressed neuronal genes, and of these we verify miR-127 binding to Psmd3. Finally, we report reduced expression of miR-127 in human stroke brains. Our results underline the impact of peripheral inflammation on the outcome of stroke in aged subjects and pinpoint molecular targets for restoring endogenous neuronal capacity to combat ischemic stroke.Peer reviewe

Magnetotelluric 3D inversion - a recapitulation of two successful workshop on forward and inversion code testing and comparison

Over the last half decade the need for, and importance of, three-dimensional (3-D) modelling of magnetotelluric (MT) data have increased dramatically and various 3-D forward and inversion codes are in use and some have become commonly available. Comparison of forward responses and inversion results is an important step for code testing and validation prior to 'production' use. The various codes use different mathematical approximations to the problem (finite differences, finite elements or integral equations), various orientations of the coordinate system, different sign conventions for the time dependence and various inversion strategies. Additionally, the obtained results are dependent on data analysis, selection and correction as well as on the chosen mesh, inversion parameters and regularization adopted, and therefore, a careful and knowledge-based use of the codes is essential. In 2008 and 2011, during two workshops at the Dublin Institute for Advanced Studies over 40 people from academia (scientists and students) and industry from around the world met to discuss 3-D MT inversion. These workshops brought together a mix of code writers as well as code users to assess the current status of 3-D modelling, to compare the results of different codes, and to discuss and think about future improvements and new aims in 3-D modelling. To test the numerical forward solutions, two 3-D models were designed to compare the responses obtained by different codes and/or users. Furthermore, inversion results of these two data sets and two additional data sets obtained from unknown models (secret models) were also compared. In this manuscript the test models and data sets are described (supplementary files are available) and comparisons of the results are shown. Details regarding the used data, forward and inversion parameters as well as computational power are summarized for each case, and the main discussion points of the workshops are reviewed. In general, the responses obtained from the various forward models are comfortingly very similar, and discrepancies are mainly related to the adopted mesh. For the inversions, the results show how the inversion outcome is affected by distortion and the choice of errors, as well as by the completeness of the data set. We hope that these compilations will become useful not only for those that were involved in the workshops, but for the entire MT community and also the broader geoscience community who may be interested in the resolution offered by MT