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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Kolesar, Tiffany A.;

    Generalized Anxiety Disorder (GAD) is a highly prevalent anxiety disorder, characterized by chronic, excessive worry. Physical symptoms are prevalent in GAD, but physiological data are often inconsistent. The goal of the present research is to investigate the neural responses to threat in GAD versus healthy controls (HC). To achieve this goal, we collected data from the largest span of the central nervous system to-date, using functional magnetic resonance imaging (fMRI). This work was broken down into the following three aims: to identify neural activity differences between GAD and HC groups in response to threat in Aim 1) the brain, Aim 2) the cervical spinal cord, and Aim 3) the thoracic spinal cord. All three aims use data acquired from a single sample of 16 participants with GAD and 14 HC. The thesis begins with an introduction to relevant topics including GAD, physiology, and MRI technology. Aim 1) is addressed in two parts. Aim 1a is an in-depth systematic review and meta-analysis on previous neuroimaging research to identify the known neural correlates of GAD, yielding results from the dorsolateral prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and culmen of the cerebellum, among others. Aim 1b includes a brain fMRI study in which GAD and HC participants view emotion-evoking images. First, region-of-interest analyses are conducted using regions identified in the systematic review, but results are not significant for these analyses. A follow-up whole brain analysis yields significant results for the main effect of group, corroborating many of the findings from the systematic review. Aims 2 and 3 are considered together in an identical fMRI task as Aim 1b, this time looking at the cervical and thoracic spinal cord. Spinal cord results include increased activity in ventral rostral cervical cord (innervating the neck, shoulders, and trapezius muscles) and mediolateral thoracic cord (innervating the adrenal medulla and gut) for the GAD group as compared to HC. These results provide neurological evidence for increased muscle tension and autonomic activity in the gut and adrenal glands for those with GAD. This work provides the most comprehensive fMRI study of the neurophysiological underpinnings of GAD to-date.

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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ MSpace at the Univer...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Madan, Christopher R.;
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Frontiers in Human N...arrow_drop_down
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Frontiers in Human N...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Combrisson, Etienne; Vallat, Raphael; Eichenlaub, Jean-Baptiste; O'Reilly, Christian; +4 Authors

    We introduce Sleep, a new Python open-source graphical user interface (GUI) dedicated to visualization, scoring and analyses of sleep data. Among its most prominent features are: (1) Dynamic display of polysomnographic data, spectrogram, hypnogram and topographic maps with several customizable parameters, (2) Implementation of several automatic detection of sleep features such as spindles, K-complexes, slow waves, and rapid eye movements (REM), (3) Implementation of practical signal processing tools such as re-referencing or filtering, and (4) Display of main descriptive statistics including publication-ready tables and figures. The software package supports loading and reading raw EEG data from standard file formats such as European Data Format, in addition to a range of commercial data formats. Most importantly, Sleep is built on top of the VisPy library, which provides GPU-based fast and high-level visualization. As a result, it is capable of efficiently handling and displaying large sleep datasets. Sleep is freely available (http://visbrain.org/sleep) and comes with sample datasets and an extensive documentation. Novel functionalities will continue to be added and open-science community efforts are expected to enhance the capacities of this module.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Frontiers in Neuroin...arrow_drop_down
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Ippolitov, Danyyl;

    Introduction: HER2+ (ErbB2+) breast cancer (BC) patients demonstrate a high incidence (30%) of brain metastases (BM). Regardless of the effectiveness of ErbB2 targeting therapies in the therapy of primary HER2+ BC, BM remains a fatal complication. Restricted drug permeability across the blood-brain barrier and specific tumor- and/or brain tumor microenvironment (TME)-derived factors determine the low effectiveness of ErbB targeted drugs in the brain. Neuregulin-1 (NRG-1) is a member of the EGF family which is commonly expressed by cells in the brain TME. NRG1 can bind to ErbB3 and/or ErbB4 receptors and potentially promote activation of alternative signaling pathways under ErbB2 inhibition. Results: The newly established patient-derived HER2+ BC model (BCBM94) that metastasizes to the brain in mice forms well-circumscribed proliferative tumors that are vascularized and surrounded by activated astrocytes. BCBM94 cells are sensitive to the pro-apoptotic actions of the reversible EGFR/ErbB2 small molecule tyrosine kinase inhibitor Lapatinib. NRG1 mitigated cytotoxicity induced by Lapatinib, as shown by higher viability in WST-1 assays and the preserved ability for long-term cell propagation in clonogenicity assays. NRG-1 blocked Lapatinib-driven PARP cleavage and activation of the pro-apoptotic caspases-3/7 and caspase-9. NRG-1 also prevented Lapatinib-induced mitochondrial damage. rhNRG1 rescued phosphorylation of kinase-impaired ErbB3 under combined Lapatinib/rhNRG1 treatment suggesting the involvement of ErbB3 in maintaining the viability of BCBM94 under Lapatinib. The essential role of ErbB3 in the apoptosis inhibiting action of rhNRG1 was confirmed by siRNA-mediated silencing (KD) of the receptor. Upon ErbB3 knockdown, rhNRG1 was no longer able to attenuate the Lapatinib-mediated apoptosis in BCBM94 and this coincided with the mitigated rescue of Survivin and XIAP expression and BAD phosphorylation in BCBM94. These rhNRG1-mediated anti-apoptotic actions were also prevented with exposure to the multi-targeted PI3K-Akt and mTORC1/C2 inhibitor (PI-103) confirming the role of the ErbB3-Akt-mTOR signaling axis in the cell viability rescue. Conclusion: The findings identify BCBM94 as a valuable brain metastasis cell model to study resistance mechanisms under ErbB2 inhibition and demonstrate an important role of NRG1 as a powerful brain TME-derived anti-apoptotic factor that can facilitate resistance of BC brain metastases to ErbB2 targeting therapies.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ MSpace at the Univer...arrow_drop_down
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Boutin, Hervé; Crossman, David; Smigova, Alison; Drake, Caroline; +22 Authors

    Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE−/−) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a “primed” inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Education and Resear...arrow_drop_down
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    Authors: Tillman, Melanie;

    Encephalitis morbidity and mortality has been a focus of public and clinical interest, especially with arboviral trends such as West Nile Virus. Worldwide, the majority of encephalitis cases have an unknown etiology. This presents a challenge for diagnosing and treating encephalitis in order to minimize long term neurological deficits or death. A literature review demonstrates a lack of information on common viral etiologies at autopsy, as well as techniques to accurately identify the viral pathogen. In this study, we defined encephalitis as lymphocytic infiltration beyond the glia limitans into brain tissue with associated microglial activation, as demonstrated by immunohistochemistry. We retrospectively reviewed the Manitoba autopsy records from 1998 to 2018 and identified 114 cases of definite or presumed viral encephalitis. Cases with encephalitis at autopsy ranged from stillborn infants to 86 years of age. Males were more affected than females. In 20 cases, a viral entity was identified. The most common proven entities were herpes simplex and polyoma virus followed by West Nile virus. Possible viral encephalitis without definitive cause likely contributed to death in 36 cases. Possible mild viral encephalitis, incidentally, identified at autopsy, was identified in 58 cases with an unrelated cause of death. In most of the severe cases a viral entity was presumed but not identified due to lack of testing or failure of testing methods. There were peaks in August and September of known WNV encephalitis. This suggests an arboviral etiology for cases of possible viral encephalitis contributing to death and incidental mild encephalitis. Developments in PCR technologies may allow increased detection and identification of viruses in cases of encephalitis which present to autopsy without a definite diagnosis, or sometimes even without clinical suspicion of encephalitis.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ MSpace at the Univer...arrow_drop_down
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    Authors: Nash, Mikyla;

    Intertidal crustaceans like Carcinus maenas shift between an osmoconforming and osmoregulating state when inhabiting full-strength seawater and dilute environments, respectively. While the bodily fluids and environment of marine osmoconformers are approximately isosmotic, osmoregulating crabs inhabiting dilute environments maintain their bodily fluid osmolality above that of their environment by actively absorbing and retaining osmolytes (e.g., Na+, Cl-, urea) while eliminating excess water. Few studies have investigated the role of aquaporins (AQPs) in the osmoregulatory organs of crustaceans, especially within brachyuran species. In the current study, three different aquaporins were identified within a transcriptome of C. maenas, including a classical AQP (CmAQP1), an aquaglyceroporin (CmGLP1), and a big-brain protein (CmBIB1), all of which are expressed in the gills and the antennal glands. Functional expression of these aquaporins confirmed water transport capabilities for CmAQP1, CmGLP1, but not for CmBIB1, while CmGLP1 also transported urea. Higher relative CmAQP1 mRNA expression within tissues of osmoconforming crabs suggests the apical/sub-apically localized channel attenuates osmotic gradients created by non- osmoregulatory processes while its downregulation in dilute media reduces the water permeability of tissues to facilitate osmoregulation. Although hemolymph urea concentrations rose upon exposure to brackish water, urea was not detected in the final urine. Due to its urea- transport capabilities, CmGLP1 is hypothesized to be involved in a urea retention mechanism believed to be involved in the production of diluted urine. Overall, these results suggest that AQPs are involved in osmoregulation and provide a basis for future mechanistic studies investigating the role of AQPs in volume regulation in crustaceans.

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    Authors: Aparajita Rahman; Eden Redman; Avary Kostiw; Jacqueline Cummine;

    Koalacademy is a language learning tool predicated on the subsequent memory effect (SME), which differentiates the brain activity between the successful or unsuccessful encoding of a studied word to memory, relaying this information back to the user in real- time. We take advantage of the SME in confirming or denying the encoding of words during the process of studying them, allowing for selective repetition of poorly studied words, thus improving the success-rate of learning. The present study is focussed on validating the underlying framework of Koalacademy, a scalable Brain Computer Interface (BCI) platform that is able to present stimuli and stream brain data in a timely fashion comparable to other traditionally validated means of obtaining electroencephalography (EEG) data from BCI headsets. The present study utilizes a comparison oddball task. We have two conditions, including a control condition using a single board computer—which brain data is streamed to and is triggered via a light sensor at the onset of stimulus on the Koalacademy platform—, and an experimental condition consisting of brain data streaming and triggered through Koalacademy. The present study is the first of two, while the latter aims to validate whether a cloud trained machine learning model based on data collected through Koalacademy is able to successfully predict subsequent recall in real-time.

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    Authors: Pauline Usuanlele; Dr Allen Chan; Landon Fuhr; Ryan Zahacy;
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    Authors: Alfasi, Abdulghader;

    Traumatic brain injury (TBI) has a 20% mortality rate and a 10-15% rate of resultant permanent disability. The consequences of TBI range from brief loss of consciousness, to prolonged coma or death. Mild TBI is amongst the common causes of admission to trauma centers all over the world. Future technologies such as magnetic resonance elastography and robotic surgery demand information about the physical properties of brain tissue. Walsh and Schettini described the mechanical behavior of brain tissue under normal status as nonlinear viscoelastic behavior and defined the associated biomechanical changes and responses in a quantitative measurement of the material changes. Yet, there is still a lack of data concerning time-dependent deformation and mechanical property changes associated with TBI. My goal in this project was to describe these mechanical responses and to create a system for measuring and evaluating the mechanical response of brain tissue in vivo. This was to be achieved by inducing cortical contusions with a calibrated weight-drop method in seventy-four young adult male Sprague-Dawley rats. Instrumented indentation was performed on control brains and 1 hour to 3 weeks after contusion with intact dura using a 4-mm-diameter flat punch indenter to a maximum depth of 1.2 mm at loading. Loading rates did not exceed 0.34 N/min and 1.2 mm/min. In order to obtain force displacement data, we studied the elastic response of the traumatized brain tissue and the deformation process (creep) during the loading and unloading of indenter. After euthanasia, the brain was removed and evaluated histologically with different methods to reveal acute and chronic changes related to the contusion. The results revealed that the biomechanical properties of the brain tissue were changed after cortical contusion. Brain tissue elasticity decreased in the edematous brain at one day following the contusion and increased at 3 weeks, in association with reactive astroglial changes. This experimental technique, combined with mathematical modeling, might eventually lead to a better understanding of the physical changes in brain following TBI.

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29 Research products
  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Kolesar, Tiffany A.;

    Generalized Anxiety Disorder (GAD) is a highly prevalent anxiety disorder, characterized by chronic, excessive worry. Physical symptoms are prevalent in GAD, but physiological data are often inconsistent. The goal of the present research is to investigate the neural responses to threat in GAD versus healthy controls (HC). To achieve this goal, we collected data from the largest span of the central nervous system to-date, using functional magnetic resonance imaging (fMRI). This work was broken down into the following three aims: to identify neural activity differences between GAD and HC groups in response to threat in Aim 1) the brain, Aim 2) the cervical spinal cord, and Aim 3) the thoracic spinal cord. All three aims use data acquired from a single sample of 16 participants with GAD and 14 HC. The thesis begins with an introduction to relevant topics including GAD, physiology, and MRI technology. Aim 1) is addressed in two parts. Aim 1a is an in-depth systematic review and meta-analysis on previous neuroimaging research to identify the known neural correlates of GAD, yielding results from the dorsolateral prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and culmen of the cerebellum, among others. Aim 1b includes a brain fMRI study in which GAD and HC participants view emotion-evoking images. First, region-of-interest analyses are conducted using regions identified in the systematic review, but results are not significant for these analyses. A follow-up whole brain analysis yields significant results for the main effect of group, corroborating many of the findings from the systematic review. Aims 2 and 3 are considered together in an identical fMRI task as Aim 1b, this time looking at the cervical and thoracic spinal cord. Spinal cord results include increased activity in ventral rostral cervical cord (innervating the neck, shoulders, and trapezius muscles) and mediolateral thoracic cord (innervating the adrenal medulla and gut) for the GAD group as compared to HC. These results provide neurological evidence for increased muscle tension and autonomic activity in the gut and adrenal glands for those with GAD. This work provides the most comprehensive fMRI study of the neurophysiological underpinnings of GAD to-date.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Madan, Christopher R.;
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    Authors: Combrisson, Etienne; Vallat, Raphael; Eichenlaub, Jean-Baptiste; O'Reilly, Christian; +4 Authors

    We introduce Sleep, a new Python open-source graphical user interface (GUI) dedicated to visualization, scoring and analyses of sleep data. Among its most prominent features are: (1) Dynamic display of polysomnographic data, spectrogram, hypnogram and topographic maps with several customizable parameters, (2) Implementation of several automatic detection of sleep features such as spindles, K-complexes, slow waves, and rapid eye movements (REM), (3) Implementation of practical signal processing tools such as re-referencing or filtering, and (4) Display of main descriptive statistics including publication-ready tables and figures. The software package supports loading and reading raw EEG data from standard file formats such as European Data Format, in addition to a range of commercial data formats. Most importantly, Sleep is built on top of the VisPy library, which provides GPU-based fast and high-level visualization. As a result, it is capable of efficiently handling and displaying large sleep datasets. Sleep is freely available (http://visbrain.org/sleep) and comes with sample datasets and an extensive documentation. Novel functionalities will continue to be added and open-science community efforts are expected to enhance the capacities of this module.

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    Authors: Ippolitov, Danyyl;

    Introduction: HER2+ (ErbB2+) breast cancer (BC) patients demonstrate a high incidence (30%) of brain metastases (BM). Regardless of the effectiveness of ErbB2 targeting therapies in the therapy of primary HER2+ BC, BM remains a fatal complication. Restricted drug permeability across the blood-brain barrier and specific tumor- and/or brain tumor microenvironment (TME)-derived factors determine the low effectiveness of ErbB targeted drugs in the brain. Neuregulin-1 (NRG-1) is a member of the EGF family which is commonly expressed by cells in the brain TME. NRG1 can bind to ErbB3 and/or ErbB4 receptors and potentially promote activation of alternative signaling pathways under ErbB2 inhibition. Results: The newly established patient-derived HER2+ BC model (BCBM94) that metastasizes to the brain in mice forms well-circumscribed proliferative tumors that are vascularized and surrounded by activated astrocytes. BCBM94 cells are sensitive to the pro-apoptotic actions of the reversible EGFR/ErbB2 small molecule tyrosine kinase inhibitor Lapatinib. NRG1 mitigated cytotoxicity induced by Lapatinib, as shown by higher viability in WST-1 assays and the preserved ability for long-term cell propagation in clonogenicity assays. NRG-1 blocked Lapatinib-driven PARP cleavage and activation of the pro-apoptotic caspases-3/7 and caspase-9. NRG-1 also prevented Lapatinib-induced mitochondrial damage. rhNRG1 rescued phosphorylation of kinase-impaired ErbB3 under combined Lapatinib/rhNRG1 treatment suggesting the involvement of ErbB3 in maintaining the viability of BCBM94 under Lapatinib. The essential role of ErbB3 in the apoptosis inhibiting action of rhNRG1 was confirmed by siRNA-mediated silencing (KD) of the receptor. Upon ErbB3 knockdown, rhNRG1 was no longer able to attenuate the Lapatinib-mediated apoptosis in BCBM94 and this coincided with the mitigated rescue of Survivin and XIAP expression and BAD phosphorylation in BCBM94. These rhNRG1-mediated anti-apoptotic actions were also prevented with exposure to the multi-targeted PI3K-Akt and mTORC1/C2 inhibitor (PI-103) confirming the role of the ErbB3-Akt-mTOR signaling axis in the cell viability rescue. Conclusion: The findings identify BCBM94 as a valuable brain metastasis cell model to study resistance mechanisms under ErbB2 inhibition and demonstrate an important role of NRG1 as a powerful brain TME-derived anti-apoptotic factor that can facilitate resistance of BC brain metastases to ErbB2 targeting therapies.

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    Authors: Boutin, Hervé; Crossman, David; Smigova, Alison; Drake, Caroline; +22 Authors

    Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE−/−) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a “primed” inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.

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    Authors: Tillman, Melanie;

    Encephalitis morbidity and mortality has been a focus of public and clinical interest, especially with arboviral trends such as West Nile Virus. Worldwide, the majority of encephalitis cases have an unknown etiology. This presents a challenge for diagnosing and treating encephalitis in order to minimize long term neurological deficits or death. A literature review demonstrates a lack of information on common viral etiologies at autopsy, as well as techniques to accurately identify the viral pathogen. In this study, we defined encephalitis as lymphocytic infiltration beyond the glia limitans into brain tissue with associated microglial activation, as demonstrated by immunohistochemistry. We retrospectively reviewed the Manitoba autopsy records from 1998 to 2018 and identified 114 cases of definite or presumed viral encephalitis. Cases with encephalitis at autopsy ranged from stillborn infants to 86 years of age. Males were more affected than females. In 20 cases, a viral entity was identified. The most common proven entities were herpes simplex and polyoma virus followed by West Nile virus. Possible viral encephalitis without definitive cause likely contributed to death in 36 cases. Possible mild viral encephalitis, incidentally, identified at autopsy, was identified in 58 cases with an unrelated cause of death. In most of the severe cases a viral entity was presumed but not identified due to lack of testing or failure of testing methods. There were peaks in August and September of known WNV encephalitis. This suggests an arboviral etiology for cases of possible viral encephalitis contributing to death and incidental mild encephalitis. Developments in PCR technologies may allow increased detection and identification of viruses in cases of encephalitis which present to autopsy without a definite diagnosis, or sometimes even without clinical suspicion of encephalitis.

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    Authors: Nash, Mikyla;

    Intertidal crustaceans like Carcinus maenas shift between an osmoconforming and osmoregulating state when inhabiting full-strength seawater and dilute environments, respectively. While the bodily fluids and environment of marine osmoconformers are approximately isosmotic, osmoregulating crabs inhabiting dilute environments maintain their bodily fluid osmolality above that of their environment by actively absorbing and retaining osmolytes (e.g., Na+, Cl-, urea) while eliminating excess water. Few studies have investigated the role of aquaporins (AQPs) in the osmoregulatory organs of crustaceans, especially within brachyuran species. In the current study, three different aquaporins were identified within a transcriptome of C. maenas, including a classical AQP (CmAQP1), an aquaglyceroporin (CmGLP1), and a big-brain protein (CmBIB1), all of which are expressed in the gills and the antennal glands. Functional expression of these aquaporins confirmed water transport capabilities for CmAQP1, CmGLP1, but not for CmBIB1, while CmGLP1 also transported urea. Higher relative CmAQP1 mRNA expression within tissues of osmoconforming crabs suggests the apical/sub-apically localized channel attenuates osmotic gradients created by non- osmoregulatory processes while its downregulation in dilute media reduces the water permeability of tissues to facilitate osmoregulation. Although hemolymph urea concentrations rose upon exposure to brackish water, urea was not detected in the final urine. Due to its urea- transport capabilities, CmGLP1 is hypothesized to be involved in a urea retention mechanism believed to be involved in the production of diluted urine. Overall, these results suggest that AQPs are involved in osmoregulation and provide a basis for future mechanistic studies investigating the role of AQPs in volume regulation in crustaceans.

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    Authors: Aparajita Rahman; Eden Redman; Avary Kostiw; Jacqueline Cummine;

    Koalacademy is a language learning tool predicated on the subsequent memory effect (SME), which differentiates the brain activity between the successful or unsuccessful encoding of a studied word to memory, relaying this information back to the user in real- time. We take advantage of the SME in confirming or denying the encoding of words during the process of studying them, allowing for selective repetition of poorly studied words, thus improving the success-rate of learning. The present study is focussed on validating the underlying framework of Koalacademy, a scalable Brain Computer Interface (BCI) platform that is able to present stimuli and stream brain data in a timely fashion comparable to other traditionally validated means of obtaining electroencephalography (EEG) data from BCI headsets. The present study utilizes a comparison oddball task. We have two conditions, including a control condition using a single board computer—which brain data is streamed to and is triggered via a light sensor at the onset of stimulus on the Koalacademy platform—, and an experimental condition consisting of brain data streaming and triggered through Koalacademy. The present study is the first of two, while the latter aims to validate whether a cloud trained machine learning model based on data collected through Koalacademy is able to successfully predict subsequent recall in real-time.

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    Authors: Pauline Usuanlele; Dr Allen Chan; Landon Fuhr; Ryan Zahacy;